Novel aminodicarboxylic acid derivatives having pharmaceutical properties

ABSTRACT

The invention relates to compounds of formulae (II), (IV), and (VI) as shown below,  
                 
wherein the several variable groups are as defined in the specification and claims. Processes for making these materials, and methods for using them in the synthesis of compounds for treatment of cardiovascular disorders and fibrotic disorders are also disclosed.

The present invention relates to novel chemical compounds whichstimulate soluble guanylate cyclase also via a novel mechanism of actionwhich proceeds without participation of the haem group of the enzyme, totheir preparation and to their use as medicaments, in particular asmedicaments for treating cardiovascular disorders.

One of the most important cellular transmission systems in mammaliancells is cyclic guanosine monophosphate (cGMP). Together with nitrogenmonoxide (NO), which is released from the endothelium and transmitshormonal and mechanical signals, it forms the NO/cGMP system. Guanylatecyclases catalyse the biosynthesis of cGMP from guanosine triphosphate(GTP). The known representatives of this family can be classified bothaccording to structural features and according to the type of ligandsinto two groups: the particular guanylate cyclases, which can bestimulated by natriuretic peptides, and the soluble guanylate cyclases,which can be stimulated by NO. The soluble guanylate cyclases consist oftwo subunits and, most likely, contain one haem per heterodimer, whichis part of the regulatory centre. It is of central importance for theactivation mechanism. NO can bind to the iron atom of the haem and thusincrease the activity of the enzyme considerably. In contrast, haem-freepreparations cannot be stimulated by NO. CO, too, is capable ofattacking the central iron atom of haem, but the stimulation by CO isconsiderably lower than that by NO.

By binding cGMP, and owing to the resulting regulation ofphosphodiesterases, ion channels and protein kinases, guanylate cyclaseplays an important rôle in various physiological processes, inparticular in the relaxation and proliferation of smooth muscle cells,in platelet aggregation and platelet adhesion and in neuronal signaltransmission, and also in disorders which are based on a disturbance ofthe abovementioned processes. Under pathophysiological conditions, theNO/cGMP system can be suppressed, which may lead, for example, tohypertension, platelet activation, increased cell proliferation,endothelial dysfunction, atherosclerosis, angina pectoris, cardiacinsufficiency, thromboses, stroke and myocardial infarct.

Owing to the expected high efficiency and few side effects, a treatmentof such disorders which targets the influence of the cGMP signal path inorganisms and is NO-independent is a promising approach.

Hitherto, for the therapeutic stimulation of soluble guanylate cyclaseuse has exclusively been made of compounds such as organic nitrateswhose effect is based on NO. This is formed by bioconversion andactivates soluble guanylate cyclase by attack at the central iron atomof haem. In addition to the side effects, the development of toleranceis one of the decisive disadvantages of this treatment.

Within the last few years, some substances have been described whichstimulate soluble guanylate cyclase directly, i.e. without prior releaseof NO, such as, for example,3-(5′-hydroxymethyl-2′-furyl)-1-benzylindazole (YC-1, Wu et al., Blood84 (1994), 4226; Mülsch et al., Br. J. Pharmacol. 120 (1997), 681),fatty acids (Goldberg et al, J. Biol. Chem. 252 (1977), 1279),diphenyliodonium hexafluorophosphate (Pettibone et al., Eur. J.Pharmacol. 116 (1985), 307), isoliquiritigenin (Yu et al., Brit. J.Pharmacol. 114 (1995), 1587), and various substituted pyrazolederivatives (WO 98/16223, WO 98/16507 and WO 98/23619).

The known stimulators of soluble guanylate cyclases stimulate the enzymeeither directly via the haem group (carbon monoxide, nitrogen monoxideor diphenyliodoniumhexafluorophosphate) by interaction with the ironcentre of the haem group and a resulting change in conformation whichleads to an increase in enzyme activity (Gerzer et al., FEBS Lett.132(1981), 71), or via a haem-dependent mechanism which is independentof NO but leads to a potentiation of the stimulating effect of NO or CO(for example YC-1, Hoenicka et al., J. Mol. Med. (1999) 14; or thepyrazole derivatives described in WO 98/16223, WO 98/16507 and WO98/23619).

The stimulating effect, asserted in the literature, of isoliquiritigeninand of fatty acids, such as, for example, arachidonic acid,prostaglandin endoperoxides and fatty acid hydroperoxides, on solubleguanylate cyclase could not be confirmed (cf., for example, Hoenicka etal., J. Mol. Med. 77 (1999), 14).

If the haem group of soluble guanylate cyclase is removed, the enzymestill shows a detectable catalytic basal activity, i.e. as before, cGMPis formed. The remaining catalytic basal activity of the haem-freeenzyme cannot be stimulated by any of the abovementioned knownstimulators.

Stimulation of haem-free soluble guanylate cyclase by protoporphyrin IXhas been described (Ignarro et al., Adv. Pharmacol. 26 (1994), 35).However, protoporphyrin IX can be considered to be a mimic of theNO-haem adduct, owing to which the addition of protoporphyrin IX tosoluble guanylate cyclase should result in the formation of an enzymestructure which corresponds to the haem-containing soluble guanylatecyclase which is stimulated by NO. This is also confirmed by the factthat the stimulating effect of protoporphyrin IX is increased by theNO-independent, but haem-dependent, stimulator YC-1 described above(Mülsch et al., Naunyn Schmiedebergs Arch. Pharmacol. 355, R47).

Thus, hitherto no compounds have been described which are capable ofstimulating soluble guanylate cyclase independently of the haem grouppresent in the enzyme.

It was an object of the present invention to develop medicaments for thetreatment of cardiovascular disorders or other disorders which can betreated by influencing the cGMP signal path in organisms.

The abovementioned object is achieved by using, for the preparation ofmedicaments, compounds which are capable of stimulating solubleguanylate cyclase also independently of NO and the haem group present inthe enzyme.

Surprisingly, it has been found that there are compounds which arecapable of stimulating soluble guanylate cyclase also independently ofthe haem group present in the enzyme. The biological activity of thesestimulators is based on an entirely novel mechanism for stimulatingsoluble guanylate cyclase. In contrast to the above-described compoundswhich are known from the prior art as stimulators of soluble guanylatecyclase, the compounds according to the invention are capable ofstimulating both the haem-containing and the haem-free form of solubleguanylate cyclase. In the case of these novel stimulators, thestimulation of the enzyme is therefore effected via a haem-independentroute, which is also confirmed by the fact that, on the one hand, thenovel stimulators do not show any synergistic action with NO at thehaem-containing enzyme and, on the other hand, the action of these novelstimulators cannot be blocked by the haem-dependent inhibitor of solubleguanylate cyclase, 1H-1,2,4-oxadiazol-(4,3a)-quinoxalin-1-one (ODQ).

This is a novel therapeutic approach for the treatment of cardiovasculardisorders and other disorders which can be treated by influencing thecGMP signal path in organisms.

EP-A-0 345 068 describes, inter alia, the aminoalkanecarboxylic acid (1)as an intermediate in the synthesis of GABA antagonists:

WO 93/00359 describes the aminoalkanecarboxylic acid (2) as anintermediate in peptide synthesis and its use as an active compound fortreating disorders of the central nervous system:

However, neither of these two publications mentions that suchaminoalkanecarboxylic acids can have a stimulating effect on solubleguanylate cyclase which is independent of the haem group present in theenzyme.

According to a preferred embodiment of the present invention, forstimulating soluble guanylate cyclase independently of the haem grouppresent in the enzyme, aminoalkanecarboxylic acids of the formula (I)are used:

-   -   in which    -   V is absent, O, NR⁴, NR⁴CONR⁴, NR⁴CO, NR⁴SO₂, COO, CONR⁴ or        S(O)_(o),        -   in which        -   R⁴ independently of any other radical R⁴ which may be            present, is hydrogen, straight-chain or branched alkyl            having up to 8carbon atoms, cycloalkyl having 3 to 8 carbon            atoms, aryl having 6 to 10 carbon atoms or arylalkyl having            7 to 18 carbon atoms, where the aryl radical for its part            may be mono- or polysubstituted by halogen, alkyl, alkoxy            having up to 6 carbon atoms,        -   o is 0, 1 or 2,    -   Q is absent, straight-chain or branched alkylene, straight-chain        or branched alkenediyl or straight-chain or branched alkinediyl        having in each case up to 12 carbon atoms, which may in each        case contain one or more groups from the group consisting of O,        S(O)_(p), NR⁵, CO, NR⁵SO₂ or CONR⁵ and which may be mono- or        polysubstituted by halogen, hydroxyl or alkoxy having up to 4        carbon atoms, where optionally any two atoms of the        abovementioned chain may be attached to one another forming a        three- to eight-membered ring,        -   in which        -   R ⁵ is hydrogen, straight-chain or branched alkyl having up            to 8 carbon atoms or cycloalkyl having 3 to 8 carbon atoms            which may be substituted by halogen or alkoxy having up to 4            carbon atoms,        -   p is 0, 1 or 2,    -   Y is hydrogen, NR⁸R⁹, aryl having 6 to 10 carbon atoms, an        aromatic or saturated heterocycle having 1 to 9 carbon atoms and        up to 3 heteroatoms from the group consisting of S, N and O or        straight-chain or branched cycloalkyl having 3 to 8 carbon        atoms, which may also be attached via N,        -   where the cyclic radicals may in each case be mono- to            trisubstituted by straight-chain or branched alkyl,            straight-chain or branched alkenyl, straight-chain or            branched alkinyl, straight-chain or branched alkoxy,            straight-chain or branched alkoxyalkoxy, straight-chain or            branched halogenoalkyl, straight-chain or branched            halogenoalkoxy having in each case up to 8 carbon atoms,            straight-chain or branched cycloalkyl having 3 to 8 carbon            atoms, halogen, hydroxyl, CN, SR⁶, NO₂, NR⁸R⁹, NR⁷COR¹⁰,            NR⁷CONR⁷R¹⁰ or CONR¹¹R¹²,        -   in which        -   R⁶ is hydrogen, straight-chain or branched alkyl having up            to 8 carbon atoms, straight-chain or branched halogenoalkyl            having up to 8 carbon atoms or cycloalkyl having 3 to 8            carbon atoms,        -   R⁷ independently of any other radical R⁷ which may be            present is hydrogen, straight-chain or branched alkyl having            up to 8 carbon atoms or cycloalkyl having 3 to 8 carbon            atoms,        -   R⁸, R⁹, R¹¹ and R¹² independently of one another are            hydrogen, straight-chain or branched alkyl, straight-chain            or branched alkenyl having up to 8 carbon atoms, aryl having            6 to 10 carbon atoms, an aromatic heterocycle having 1 to 9            carbon atoms and up to 3 heteroatoms from the group            consisting of S, N and O, arylalkyl having 8 to 18 carbon            atoms, cycloalkyl having 3 to 8 carbon atoms or a radical of            the formula SO₂R¹³,            -   where the aryl radical for its part may be mono- or                polysubstituted by halogen, hydroxyl, CN, NO₂, NH₂,                NHCOR⁷, alkyl, alkoxy, halogenoalkyl or halogenoalkoxy                having up to 6 carbon atoms,            -   or two substituents R⁸ and R⁹ or R¹¹ and R¹² may be                attached to one another forming a five- or six-membered                ring which may contain O or N,            -   in which,            -   R¹³ is straight-chain or branched alkyl having up to 4                carbon atoms or aryl having 6 to 10 carbon atoms, where                the aryl radical for its part may be mono- or                polysubstituted by halogen, CN, NO₂, alkyl, alkoxy,                halogenoalkyl or halogenoalkoxy having up to 6 carbon                atoms,        -   R¹⁰ is hydrogen, straight-chain or branched alkyl having up            to 12 carbon atoms, straight-chain or branched alkenyl            having up to 12 carbon atoms, aryl having 6 to 10 carbon            atoms, an aromatic heterocycle having 1 to 9 carbon atoms            and up to 3 heteroatoms from the group consisting of S, N            and O or cycloalkyl having 3 to 8 carbon atoms, which may            furthermore optionally be substituted by halogen, hydroxyl,            CN, NO₂, NH₂, NHCOR⁷, alkyl, alkoxy, halogenoalkyl or            halogenoalkoxy having up to 6 carbon atoms;        -   and/or the cyclic radicals may in each case be mono- to            trisubstituted by aryl having 6 to 10 carbon atoms, an            aromatic or saturated heterocycle having 1 to 9 carbon atoms            and up to 3 heteroatoms from the group consisting of S, N            and O, which may also be attached via N, which may be            attached directly or via a group O, S, SO, SO₂, NR⁷, SO₂NR⁷,            CONR⁷, straight-chain or branched alkylene, straight-chain            or branched alkenediyl, straight-chain or branched alkyloxy,            straight-chain or branched oxyalkyloxy, straight-chain or            branched sulphonylalkyl, straight-chain or branched            thioalkyl having in each case up to 8 carbon atoms and which            may be mono- to trisubstituted by straight-chain or branched            alkyl, straight-chain or branched alkoxy, straight-chain or            branched alkoxyalkoxy, straight-chain or branched            halogenoalkyl, straight-chain or branched halogenoalkoxy,            carbonylalkyl or straight-chain or branched alkenyl having            in each case up to 6 carbon atoms, halogen, SR⁶, CN, NO₂,            NR⁸R⁹, CONR¹⁵R¹⁶or NR¹⁴COR¹⁷,        -   in which        -   R¹⁴ is hydrogen, straight-chain or branched alkyl having up            to 8 carbon atoms or cycloalkyl having 3 to 8 carbon atoms,        -   R¹⁵, R¹⁶ independently of one another are hydrogen,            straight-chain or branched alkyl having up to 8 carbon            atoms, cycloalkyl having 3 to 8 carbon atoms, aryl having 6            to 10carbon atoms or a radical of the formula SO₂R¹⁸, where            the aryl radical for its part may be mono- or            polysubstituted by halogen, hydroxyl, CN, NO₂, NH₂, NHCOR⁷,            alkyl, alkoxy, halogenoalkyl or halogenoalkoxy having up to            6 carbon atoms,            -   in which            -   R¹⁸ is straight-chain or branched alkyl having up to 4                carbon atoms or aryl having 6 to 10 carbon atoms,                -   where the aryl radical for its part may be mono- or                    polysubstituted by halogen, hydroxyl, CN, NO₂, NH₂,                    NHCOR⁷, alkyl, alkoxy, halogenoalkyl or                    halogenoalkoxy having up to 6 carbon atoms,        -   and        -   R¹⁷ is hydrogen, straight-chain or branched alkyl having up            to 12 carbon atoms, straight-chain or branched alkenyl            having up to 12 carbon atoms, aryl having 6 to 10 carbon            atoms, an aromatic heterocycle having 1 to 9 carbon atoms            and up to 3 heteroatoms from the group consisting of S, N            and O or cycloalkyl having 3 to 8 carbon atoms, which may            furthermore optionally be substituted by halogen, hydroxyl,            CN, NO₂, NH₂, NHCOR⁷, alkyl, alkoxy, halogenoalkyl or            halogenoalkoxy having up to 6 carbon atoms;        -   and/or the cyclic radicals may be fused with an aromatic or            saturated carbocycle having 1 to 10 carbon atoms or an            aromatic or saturated heterocycle having 1 to 9 carbon atoms            and up to 3 heteroatoms from the group consisting of S, N            and O,    -   R³ is hydrogen, halogen, straight-chain or branched alkyl,        straight-chain or branched halogenoalkyl, straight-chain or        branched alkoxy, or alkoxycarbonyl having in each case up to 4        carbon atoms, CN, NO₂ or NR¹⁹R²⁰,        -   in which        -   R¹⁹ and R²⁰ independently of one another are hydrogen,            straight-chain or branched alkyl having up to 4 carbon atoms            or cycloalkyl having 3 to 8 carbon atoms,    -   m is an integer from 1 to 4,    -   W is straight-chain or branched alkylene having up to 6 carbon        atoms or straight-chain or branched alkenediyl having up to 6        carbon atoms which may in each case contain a group from the        group consisting of O, S(O)_(q), NR²¹, CO and CONR²¹, or is CO,        NHCO or OCO,        -   in which        -   q is 0, 1 or 2,        -   R²¹ is hydrogen, straight-chain or branched alkyl having up            to 8 carbon atoms or cycloalkyl having 3 to 8 carbon atoms,    -   U is straight-chain or branched alkyl having up to 4 carbon        atoms,    -   A is aryl having 6 to 10 carbon atoms or an aromatic heterocycle        having 1 to 9 carbon atoms and up to 3 heteroatoms from the        group consisting of S, N and O,        -   which may optionally be mono- to trisubstituted by halogen,            straight-chain or branched alkyl, straight-chain or branched            halogenoalkyl, straight-chain or branched alkoxy,            halogenoalkoxy or alkoxycarbonyl having up to 4 carbon            atoms, CN, NO₂ or NR²²R²³,        -   in which        -   R²² and R²³ independently of one another are each hydrogen,            straight-chain or branched alkyl having up to 8 carbon atoms            or cycloalkyl having 3 to 8 carbon atoms, carbonylalkyl or            sulphonylalkyl,    -   R² is tetrazolyl, COOR²⁴ or CONR²⁵R²⁶,        -   in which        -   R²⁴ is hydrogen, alkyl having 1 to 8 carbon atoms or            cycloalkyl having 3 to 8 carbon atoms,        -   R²⁵ and R²⁶ independently of one another are each hydrogen,            straight-chain or branched alkyl having up to 8 carbon            atoms, cycloalkyl having 3 to 8 carbon atoms or a radical of            the formula SO₂R²⁷,            -   or R²⁵ and R²⁶ together form a five- or six-membered                ring which may contain N or O,            -   in which            -   R²⁷ is straight-chain or branched alkyl having up to 4                carbon atoms or aryl having 6 to 10 carbon atoms,                -   where the aryl radical for its part may be mono- or                    polysubstituted by halogen, CN, NO₂, alkyl, alkoxy,                    halogenoalkyl or halogenoalkoxy having up to 6                    carbon atoms,    -   X is straight-chain or branched alkylene having up to 12 carbon        atoms or straight-chain or branched alkenediyl having up to 12        carbon atoms which may in each case contain one to three groups        from the group consisting of O, S(O)_(r), NR²⁸, CO or CONR²⁹,        aryl or aryloxy having 6 to 10 carbon atoms, where the aryl        radical for its part may be mono- or polysubstituted by halogen,        CN, NO₂, alkyl, alkoxy, halogenoalkyl or halogenoalkoxy having        up to 6 carbon atoms, where optionally any two atoms of the        abovementioned chains are attached to one another via an alkyl        chain, forming a three- to eight-membered ring,        -   in which        -   r is 0, 1 or 2,        -   R²⁸ is hydrogen, alkyl having 1 to 8 carbon atoms or            cycloalkyl having 3 to 8 carbon atoms,        -   R²⁹ is hydrogen, straight-chain or branched alkyl having up            to 8 carbon atoms or cycloalkyl having 3 to 8 carbon atoms,    -   n is 1 or 2,    -   R¹ is tetrazolyl, COOR³⁰ or CONR³¹R³²,        -   in which        -   R³⁰ is hydrogen, alkyl having 1 to 8 carbon atoms or            cycloalkyl having 3 to 8 carbon atoms,        -   R³¹ and R³² independently of one another are each hydrogen,            straight-chain or branched alkyl having up to 8 carbon            atoms, cycloalkyl having 3 to 8 carbon atoms or a radical of            the formula SO₂R³³,            -   in which            -   R³³ is straight-chain or branched alkyl having up to 4                carbon atoms or aryl having 6 to 10 carbon atoms,                -   where the aryl radical for its part may be mono- or                    polysubstituted by halogen, CN, NO₂, alkyl, alkoxy,                    halogenoalkyl or halogenoalkoxy having up to 6                    carbon atoms,    -   and its stereoisomers and salts.

Preference is given here to compounds of the formula (I)

-   -   in which    -   V is absent, O, NR⁴, NR⁴CONR⁴, NR⁴CO, NR⁴SO₂, COO, CONR⁴ or        S(O)_(o),        -   in which        -   R⁴, independently of any other radical R⁴ which may be            present, is hydrogen, straight-chain or branched alkyl            having up to 8 carbon atoms, cycloalkyl having 3 to 8 carbon            atoms, aryl having 6 to 10 carbon atoms or arylalkyl having            7 to 18 carbon atoms, where the aryl radical for its part            may be mono- or polysubstituted by halogen, alkyl, alkoxy            having up to 6 carbon atoms,        -   o is 0, 1 or 2,    -   Q is absent, straight-chain or branched alkylene, straight-chain        or branched alkenediyl or straight-chain or branched alkinediyl        having in each case up to 12 carbon atoms, which may in each        case contain one or more groups from the group consisting of O,        S(O)_(p), NR⁵, CO, NR⁵SO₂ or CONR⁵ and which may be mono- or        polysubstituted by halogen, hydroxyl or alkoxy having up to 4        carbon atoms, where optionally any two atoms of the        abovementioned chain may be attached to one another forming a        three- to eight-membered ring,        -   in which        -   R⁵ is hydrogen, straight-chain or branched alkyl having up            to 8 carbon atoms or cycloalkyl having 3 to 8 carbon atoms            which may be substituted by halogen or alkoxy having up to 4            carbon atoms,        -   p is0, 1 or 2,    -   Y is hydrogen, NR⁸R⁹, aryl having 6 to 10 carbon atoms, an        aromatic or saturated heterocycle having 1 to 9 carbon atoms and        up to 3 heteroatoms from the group consisting of S, N and O or        straight-chain or branched cycloalkyl having 3 to 8 carbon        atoms, which may also be attached via N,        -   where the cyclic radicals may in each case be mono- to            trisubstituted by straight-chain or branched alkyl,            straight-chain or branched alkenyl, straight-chain or            branched alkinyl, straight-chain or branched alkoxy,            straight-chain or branched alkoxyalkoxy, straight-chain or            branched halogenoalkyl, straight-chain or branched            halogenoalkoxy having in each case up to 8 carbon atoms,            straight-chain or branched cycloalkyl having 3 to 8 carbon            atoms, halogen, hydroxyl, CN, SR⁶, NO₂, NR⁸R⁹, NR⁷COR¹⁰,            NR⁷CONR⁷R¹⁰ or CONR¹¹R¹²,        -   in which        -   R⁶ is hydrogen, straight-chain or branched alkyl having up            to 8 carbon atoms, straight-chain or branched halogenoalkyl            having up to 8 carbon atoms or cycloalkyl having 3 to 8            carbon atoms,        -   R⁷ independently of any other radical R⁷ which may be            present is hydrogen, straight-chain or branched alkyl having            up to 8 carbon atoms or cycloalkyl having 3 to 8 carbon            atoms,        -   R⁸, R⁹, R¹¹ and R¹² independently of one another are            hydrogen, straight-chain or branched alkyl, straight-chain            or branched alkenyl having up to 8 carbon atoms, aryl having            6 to 10 carbon atoms, an aromatic heterocycle having 1 to 9            carbon atoms and up to 3 heteroatoms from the group            consisting of S, N and O, arylalkyl having 8 to 18 carbon            atoms, cycloalkyl having 3 to 8 carbon atoms or a radical of            the formula SO₂R¹³,            -   where the alkyl radical for its part may be mono- or                polysubstituted by halogen, hydroxyl, CN, NO₂, NH₂,                NHCOR⁷, alkyl, alkoxy, halogenoalkyl or halogenoalkoxy                having up to 6 carbon atoms,            -   or two substituents R⁸ and R⁹ or R¹¹ and R¹² may be                attached to one another forming a five- or six-membered                ring which may contain O or N,            -   in which,            -   R¹³ is straight-chain or branched alkyl having up to 4                carbon atoms or aryl having 6 to 10 carbon atoms, where                the aryl radical for its part may be mono- or                polysubstituted by halogen, CN, NO₂, alkyl, alkoxy,                halogenoalkyl or halogenoalkoxy having up to 6 carbon                atoms,        -   R¹⁰ is hydrogen, straight-chain or branched alkyl having up            to 12 carbon atoms, straight-chain or branched alkenyl            having up to 12 carbon atoms, aryl having 6 to 10 carbon            atoms, an aromatic heterocycle having 1 to 9 carbon atoms            and up to 3 heteroatoms from the group consisting of S, N            and O or cycloalkyl having 3 to 8 carbon atoms, which may            furthermore optionally be substituted by halogen, hydroxyl,            CN, NO₂, NH₂, NHCOR⁷, alkyl, alkoxy, halogenoalkyl or            halogenoalkoxy having up to 6 carbon atoms;        -   and/or the cyclic radicals may in each case be mono- to            trisubstituted by aryl having 6 to 10 carbon atoms, an            aromatic or saturated heterocycle having 1 to 9 carbon atoms            and up to 3 heteroatoms from the group consisting of S, N            and O, which may also be attached via N, which may be            attached directly or via a group O, S, SO, SO₂, NR⁷, SO₂NR⁷,            CONR⁷, straight-chain or branched alkylene, straight-chain            or branched alkenediyl, straight-chain or branched alkyloxy,            straight-chain or branched oxyalkyloxy, straight-chain or            branched sulphonylalkyl, straight-chain or branched            thioalkyl having in each case up to 8 carbon atoms and which            may be mono- to trisubstituted by straight-chain or branched            alkyl, straight-chain or branched alkoxy, straight-chain or            branched alkoxyalkoxy, straight-chain or branched            halogenoalkyl, straight-chain or branched halogenoalkoxy,            carbonylalkyl or straight-chain or branched alkenyl having            in each case up to 6 carbon atoms, halogen, SR⁶, CN, NO₂,            NR⁸R⁹, CONR¹⁵R¹⁶or NR¹⁴COR¹⁷,        -   in which        -   R¹⁴ is hydrogen, straight-chain or branched alkyl having up            to 8 carbon atoms or cycloalkyl having 3 to 8 carbon atoms,        -   R¹⁵, R¹⁶ independently of one another are hydrogen,            straight-chain or branched alkyl having up to 8 carbon            atoms, cycloalkyl having 3 to 8 carbon atoms or a radical of            the formula SO₂R¹⁸,            -   in which            -   R¹⁸ is straight-chain or branched alkyl having up to 4                carbon atoms or aryl having 6 to 10 carbon atoms,                -   where the aryl radical for its part may be mono- or                    polysubstituted by halogen, CN, NO₂, alkyl, alkoxy,                    halogenoalkyl or halogenoalkoxy having up to 6                    carbon atoms,        -   and        -   R¹⁷ is hydrogen, straight-chain or branched alkyl having up            to 12 carbon atoms, straight-chain or branched alkenyl            having up to 12 carbon atoms, aryl having 6 to 10 carbon            atoms, an aromatic heterocycle having 1 to 9 carbon atoms            and up to 3 heteroatoms from the group consisting of S, N            and O or cycloalkyl having 3 to 8 carbon atoms, which may            furthermore optionally be substituted by halogen, CN, NO₂,            alkyl, alkoxy, halogenoalkyl or halogenoalkoxy having up to            6 carbon atoms,        -   and/or the cyclic radicals may be fused with an aromatic or            saturated carbocycle having 1 to 10 carbon atoms or an            aromatic or saturated heterocycle having 1 to 9 carbon atoms            and up to 3 heteroatoms from the group consisting of S, N            and O,    -   R³ is hydrogen, halogen, straight-chain or branched alkyl,        straight-chain or branched halogenoalkyl or straight-chain or        branched alkoxy having in each case up to 4 carbon atoms,    -   m is an integer from 1 to 4,    -   W is straight-chain or branched alkylene or straight-chain or        branched alkenediyl having in each case up to 4 carbon atoms,    -   U is —CH₂—,    -   A is phenyl or an aromatic heterocycle having 1 to 9 carbon        atoms and up to 3 heteroatoms from the group consisting of S, N        and O, which may optionally be mono- to trisubstituted by        halogen, straight-chain or branched alkyl, straight-chain or        branched halogenoalkyl or straight-chain or branched alkoxy        having up to 4 carbon atoms,    -   R² is COOR²⁴,        -   in which        -   R²⁴ is hydrogen or straight-chain or branched alkyl having            up to 6 carbon atoms,    -   X is straight-chain or branched alkylene having up to 8 carbon        atoms or straight-chain or branched alkenediyl having up to 8        carbon atoms which may in each case contain one to three groups        from the group consisting of phenyl, phenyloxy, O, CO and        CONR²⁹,        -   in which        -   R²⁹ is hydrogen, straight-chain or branched alkyl having up            to 6 carbon atoms or cycloalkyl having 3 to 6 carbon atoms,    -   n is 1 or 2,    -   R¹ is COOR³⁰,        -   in which        -   R³⁰ is hydrogen or straight-chain or branched alkyl having            up to 6 carbon atoms.

Particular preference is given to compounds of the formula (I)

-   -   in which    -   V is absent, O, S or NR⁴,        -   in which        -   R⁴ is hydrogen or methyl,    -   Q is absent, straight-chain or branched alkylene having up to 9        carbon atoms or straight-chain or branched alkenediyl or        straight-chain or branched alkinediyl having up to 4 carbon        atoms which may be monosubstituted by halogen,    -   Y is H, NR⁸R⁹, cyclohexyl, phenyl, naphtyl or a heterocycle from        the group consisting of        -   which may also be attached via N,        -   where the cyclic radicals may in each case be mono- to            trisubstituted by straight-chain or branched alkyl,            straight-chain or branched alkenyl, straight-chain or            branched alkinyl, straight-chain or branched alkoxy,            straight-chain or branched alkoxyalkoxy, straight-chain or            branched halogenoalkyl, straight-chain or branched            halogenoalkoxy having in each case up to 4 carbon atoms,            straight-chain or branched cycloalkyl having 3 to 6 carbon            atoms, F, Cl, Br, I, NO₂, SR⁶, NR⁸R⁹, NR⁷COR¹⁰ or CONR¹¹R¹²,        -   in which        -   R⁶ is hydrogen, straight-chain or branched alkyl having up            to 8 carbon atoms, or straight-chain or branched            halogenoalkyl having up to 4 carbon atoms,        -   R⁷ is hydrogen, or straight-chain or branched alkyl having            up to 4 carbon atoms,        -   R⁸, R⁹, R¹¹ and R¹² independently of one another are            hydrogen, straight-chain or branched alkyl having up to 4            carbon atoms or phenyl,            -   where the phenyl radical may be mono- to trisubstituted                by F, Cl Br, hydroxyl, methyl, ethyl, n-propyl,                i-propyl, n-butyl, s-butyl, i-butyl, t-butyl, methoxy,                ethoxy, amino, acetylamino, NO₂, CF₃, OCF₃ or CN,            -   or two substituents R⁸ and R⁹ or R¹¹ and R¹² may be                attached to one another forming a five- or six-membered                ring which may be interrupted by O or N,        -   R¹⁰ is hydrogen, straight-chain or branched alkyl having up            to 4 carbon atoms or phenyl,            -   where the phenyl radical may be mono- to trisubstituted                by F, Cl Br, hydroxyl, methyl, ethyl, n-propyl,                i-propyl, n-butyl, s-butyl, i-butyl, t-butyl, methoxy,                ethoxy, amino, acetylamino, NO₂, CF₃, OCF₃ or CN;        -   and/or the cyclic radicals may in each case be mono- to            trisubstituted by phenyl or a heterocycle from the group            consisting of        -   which may be attached directly or via a group O, S, SO, SO₂,            NR⁴, SO₂NR⁷, CONR⁷, straight-chain or branched alkylene,            straight-chain or branched alkenediyl, straight-chain or            branched alkyloxy, straight-chain or branched oxyalkyloxy,            straight-chain or branched sulphonylalkyl, straight-chain or            branched thioalkyl having in each case 4 carbon atoms and            which may be mono- to trisubstituted by straight-chain or            branched alkyl, straight-chain or branched alkoxy,            straight-chain or branched alkoxyalkoxy, straight-chain or            branched halogenoalkyl or straight-chain or branched alkenyl            having in each case up to 4 carbon atoms, F, Cl, Br, I, CN,            SCH₃, OCF₃, NO₂, NR⁸R⁹ or NR¹⁴COR¹⁷,        -   in which        -   R¹⁴ is hydrogen, straight-chain or branched alkyl having up            to 8 carbon atoms, or cycloalkyl having 3 to 8 carbon atoms,        -   and        -   R¹⁷ is hydrogen, straight-chain or branched alkyl having up            to 12 carbon atoms, straight-chain or branched alkenyl            having up to 12 carbon atoms, aryl having 6 to 10 carbon            atoms, an aromatic heterocycle having 1 to 9 carbon atoms            and up to 3 heteroatoms from the group consisting of S, N            and O or cycloalkyl having 3 to 8 carbon atoms, which may            furthermore optionally be substituted by F, Cl Br, hydroxyl,            methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl,            i-butyl, t-butyl, methoxy, ethoxy, amino, acetylamino, NO₂,            CF₃, OCF₃ or CN;        -   and/or the cyclic radicals may be fused with an aromatic or            saturated carbocycle having 1 to 10 carbon atoms or an            aromatic or saturated heterocycle having 1 to 9 carbon atoms            and up to 3 heteroatoms from the group consisting of S, N            and O,    -   R³ is hydrogen or fluorine,    -   m is an integer from 1 to 4,    -   W is CH₂, —CH₂CH₂—, CH₂CH₂CH₂, CH═CHCH₂,    -   U is —CH₂—,    -   A is phenyl, pyridyl, thienyl or thiazolyl which may optionally        be mono- to trisubstituted by methyl, ethyl, n-propyl, i-propyl,        n-butyl, i-butyl, s-butyl, t-butyl, CF₃, methoxy, ethoxy, F, Cl,        Br,    -   R² is COOR²⁴,        -   in which        -   R²⁴ is hydrogen or straight-chain or branched alkyl having            up to 4 carbon atoms,    -   X is straight-chain or branched alkylene having up to 8 carbon        atoms or straight-chain or branched alkenediyl having up to 8        carbon atoms which may in each case contain one to three groups        from the group consisting of phenyl, phenyloxy, O, CO and        CONR²⁹,        -   in which        -   R²⁹ is hydrogen, straight-chain or branched alkyl having up            to 6 carbon atoms or cycloalkyl having 3 to 6 carbon atoms,    -   n is 1 or 2,    -   R¹ is COOR³⁵,        -   in which        -   R³⁵ is hydrogen or straight-chain or branched alkyl having            up to 6 carbon atoms.

Very particular preference is given here to compounds of the formula(I),

-   -   in which    -   V is 0,    -   Q is straight-chain or branched alkylene having up to 9 carbon        atoms or straight-chain or branched alkenediyl or straight-chain        or branched alkinediyl having up to 4 carbon atoms which may be        monosubstituted by halogen,    -   Y is H, cyclohexyl, phenyl or a heterocycle from the group        consisting of    -   where the cyclic radicals may in each case be mono- to        trisubstituted by straight-chain or branched alkyl,        straight-chain or branched alkenyl, straight-chain or branched        alkinyl, straight-chain or branched alkoxy, straight-chain or        branched alkoxyalkoxy, straight-chain or branched halogenoalkyl,        straight-chain or branched halogenoalkoxy having in each case up        to 4 carbon atoms, straight-chain or branched cycloalkyl having        3 to 6 carbon atoms, F, Cl, Br, I, NO₂, SR⁶, NR⁸R⁹, NR⁷COR¹⁰ or        CONR¹¹R¹²,        -   in which        -   R⁶ is hydrogen, straight-chain or branched alkyl having up            to 4 carbon atoms or straight-chain or branched            halogenoalkyl having up to 4 carbon atoms,        -   R⁷ is hydrogen, or straight-chain or branched alkyl having            up to 4 carbon atoms,        -   R⁸, R⁹, R¹¹ and R¹² independently of one another are            hydrogen, straight-chain or branched alkyl having up to 4            carbon atoms or phenyl,            -   where the phenyl radical may be mono- to trisubstituted                by F, Cl Br, hydroxyl, methyl, ethyl, n-propyl,                i-propyl, n-butyl, s-butyl, i-butyl, t-butyl, methoxy,                ethoxy, amino, acetylamino, NO₂, CF₃, OCF₃ or CN,            -   or two substituents R⁸ and R⁹ or R¹¹ and R¹² may be                attached to one another forming a five- or six-membered                ring which may be interrupted by O or N,        -   R¹⁰ is hydrogen, straight-chain or branched alkyl having up            to 4 carbon atoms or phenyl,            -   where the phenyl radical may be mono- to trisubstituted                by F, Cl Br, hydroxyl, methyl, ethyl, n-propyl,                i-propyl, n-butyl, s-butyl, i-butyl, t-butyl, methoxy,                ethoxy, amino, acetylamino, NO₂, CF₃, OCF₃ or CN;        -   and/or the cyclic radicals may in each case be mono- to            trisubstituted by phenyl or a heterocycle from the group            consisting of        -   which may be attached directly or via a group O, S, SO, SO₂,            straight-chain or branched alkylene, straight-chain or            branched alkenediyl, straight-chain or branched alkyloxy,            straight-chain or branched oxyalkyloxy, straight-chain or            branched sulphonylalkyl, straight-chain or branched            thioalkyl having in each case up to 4 carbon atoms and which            may be mono- to trisubstituted by straight-chain or branched            alkyl, straight-chain or branched alkoxy, straight-chain or            branched alkoxyalkoxy, straight-chain or branched            halogenoalkyl or straight-chain or branched alkenyl having            in each case up to 4 carbon atoms, F, Cl, Br, I, CN, SCH₃,            OCF₃, NO₂, NR⁸R⁹ or NR¹⁴COR¹⁷,        -   in which        -   R¹⁴ is hydrogen, straight-chain or branched alkyl having up            to 6 carbon atoms or cycloalkyl having 3 to 6 carbon atoms,        -   and        -   R¹⁷ is hydrogen, straight-chain or branched alkyl having up            to 6 carbon atoms, straight-chain or branched alkenyl having            up to 6 carbon atoms, aryl having 6 to 10 carbon atoms, an            aromatic heterocycle having 1 to 9 carbon atoms and up to 3            heteroatoms from the group consisting of S, N and O or            cycloalkyl having 3 to 6 carbon atoms, which may furthermore            optionally be substituted by F, Cl, Br, hydroxyl, methyl,            ethyl, n-propyl, i-propyl, n-butyl, s-butyl, i-butyl,            t-butyl, methoxy, ethoxy, amino, acetylamino, NO₂, CF₃, OCF₃            or CN;        -   and/or the cyclic radicals may be fused with an aromatic or            saturated carbocycle having 1 to 10 carbon atoms or an            aromatic or saturated heterocycle having 1 to 9 carbon atoms            and up to 3 heteroatoms from the group consisting of S, N            and O,    -   R³ is hydrogen or fluorine,    -   m is an integer from 1 to 2,    -   W is —CH₂— or —CH₂CH₂—,    -   U is —CH₂—,    -   A is phenyl which may optionally be mono- to trisubstituted by        methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl,        t-butyl, CF₃, methoxy, ethoxy, F, Cl, Br,    -   R² is COOR²⁴,        -   in which        -   R²⁴ is hydrogen or straight-chain or branched alkyl having            up to 4 carbon atoms,    -   X is straight-chain or branched alkylene having up to 6 carbon        atoms or straight-chain or branched alkenediyl having up to 6        carbon atoms, which may each contain one to three groups from        the group consisting of phenyloxy, O, CO and CONR²⁹,        -   in which        -   R²⁹ is hydrogen, straight-chain or branched alkyl having up            to 6 carbon atoms or cycloalkyl having 3 to 6 carbon atoms,    -   n is 1 or 2,    -   R¹ is COOR³⁵,        -   in which        -   R³⁵ is hydrogen or straight-chain or branched alkyl having            up to 4 carbon atoms.

Particular preference according to the invention is given to compoundsof the formula (I), in which R¹ and R² are each COOH.

Very particular preference according to the present invention is givento compounds in which

-   -   V is 0,    -   Q is CH₂,    -   Y is phenyl which is substituted by a radical selected from the        group consisting of 2-phenylethyl, cyclohexyl, 4-chlorophenyl,        4-methoxyphenyl, 4-trifluoromethylphenyl, 4-cyanophenyl,        4-chlorophenoxy, 4-methoxyphenoxy, 4-trifluoromethylphenoxy,        4-cyanophenoxy, 4-methylphenyl,    -   R³ is hydrogen or fluorine,    -   m is an integer from 1 to 2,    -   W is —CH₂CH₂—,    -   U is —CH₂—,    -   A is phenyl,    -   R² is COOH, where R² is located in the 4-position to the radical        U,    -   X is (CH₂)₄,    -   R¹ is COOH.

The compounds of the general formula (I) according to the invention mayalso be present in the form of their salts. In general, salts withorganic or inorganic bases or acids may be mentioned here.

In the context of the present invention, preference is given tophysiologically acceptable salts. Physiologically acceptable salts ofthe compounds according to the invention may be salts of the substancesaccording to the invention with mineral acids, carboxylic acids orsulphonic acids. Particular preference is given, for example, to saltswith hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoricacid, methanesulphonic acid, ethanesulphonic acid, p-toluenesulphonicacid, benzenesulphonic acid, naphthalenedisulphonic acid, acetic acid,propionic acid, lactic acid, tartaric acid, citric acid, fumaric acid,maleic acid or benzoic acid.

Physiologically acceptable salts may also be the metal or ammonium saltsof the compounds according to the invention which have a free carboxylgroup. Particular preference is given, for example, to sodium,potassium, magnesium or calcium salts, and to ammonium salts which arederived from ammonia, or organic amines, such as, for example,ethylamine, di- or triethylamine, di- or triethanolamine,dicyclohexylamine, dimethylaminoethanol, arginine, lysine orethylenediamine.

The compounds according to the invention may exist in stereoisomericforms which are either like image and mirror image (enantiomers) orwhich are not like image and mirror image (diastereomers). The inventionrelates both to the enantiomers or diastereomers and to their respectivemixtures. The racemates, like the diastereomers, can be separated intostereoisomerically uniform components in a known manner, for example byoptical resolution or chromatographic separation. Any double bondspresent in the compounds according to the invention can be present inthe cis or trans configuration (Z or E form).

In the context of the present invention, the substituents generallyhave, unless indicated otherwise, the following meanings:

Alkyl generally represents a straight-chain or branched hydrocarbonradical having 1 to 20 carbon atoms. Examples which may be mentioned aremethyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl,hexyl, isohexyl, heptyl, isoheptyl, octyl and isooctyl, nonyl, decyl,dodecyl, eicosyl.

Alkylene generally represents a straight-chain or branched hydrocarbonbridge having 1 to 20 carbon atoms. Examples which may be mentioned aremethylene, ethylene, propylene, (α-methylethylene, β-methylethylene,α-ethylethylene, β-ethylethylene, butylene, α-methylpropylene,β-methylpropylene, γ-methylpropylene, α-ethylpropylene,β-ethylpropylene, γ-ethylpropylene, pentylene, hexylene, heptylene,octylene, nonylene, decylene, dodeylene and eicosylene.

Alkenyl generally represents a straight-chain or branched hydrocarbonradical having 2 to 20 carbon atoms and one or more, preferably one ortwo, double bonds. Examples which may be mentioned are allyl, propenyl,isopropenyl, butenyl, isobutenyl, pentenyl, isopentenyl, hexenyl,isohexenyl, heptenyl, isoheptenyl, octenyl, isooctenyl. Alkinylgenerally represents a straight-chain or branched hydrocarbon radicalhaving 2 to 20 carbon atoms and one or more, preferably one or two,triple bonds. Examples which may be mentioned are ethinyl, 2-butinyl,2-pentinyl and 2-hexinyl.

Alkenediyl generally represents a straight-chain or branched hydrocarbonbridge having 2 to 20 carbon atoms and one or more, preferably one ortwo, double bonds. Examples which may be mentioned are ethene-1,2-diyl,propene-1,3-diyl, propene-1,2-diyl, 1-butene-1,4-diyl,1-butene-1,3-diyl, 1-butene-1,2-diyl, 2-butene-1,4-diyl,2-butene-1,3-diyl, 2-butene-2,3-diyl.

Alkinediyl generally represents a straight-chain or branched hydrocarbonbridge having 2 to 20 carbon atoms and one or more, preferably one ortwo, triple bonds. Examples which may be mentioned are ethine-1,2-diyl,propine-1,3-diyl, 1-butine-1,4-diyl, 1-butine-1,3-diyl,2-butene-1,4-diyl.

Acyl generally represents straight-chain or branched lower alkyl having1 to 9 carbon atoms which is attached via a carbonyl group. Exampleswhich may be mentioned are: acetyl, ethylcarbonyl, propylcarbonyl,isopropylcarbonyl, butylcarbonyl and isobutylcarbonyl.

Alkoxy generally represents a straight-chain or branched hydrocarbonradical having 1 to 14 carbon atoms which is attached via an oxygenatom. Examples which may be mentioned are methoxy, ethoxy, propoxy,isopropoxy, butoxy, isobutoxy, pentoxy, isopentoxy, hexoxy, isohexoxy,heptoxy, isoheptoxy, octoxy or isooctoxy. The terms “alkoxy” and“alkyloxy” are used synonymously.

Alkoxyalkyl generally represents an alkyl radical having up to 8 carbonatoms which is substituted by an alkoxy radical having up to 8 carbonatoms.

Alkoxycarbonyl can be depicted, for example, by the formula

Alkyl here generally represents a straight-chain or branched hydrocarbonradical having 1 to 13 carbon atoms. The following alkoxycarbonylradicals may be mentioned as examples: methoxycarbonyl, ethoxycarbonyl,propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl orisobutoxycarbonyl.

Cycloalkyl generally represents a cyclic hydrocarbon radical having 3 to8 carbon atoms. Preference is given to cyclopropyl, cyclopentyl andcyclohexyl. Examples which may be mentioned are cyclopentyl, cyclohexyl,cycloheptyl and cyclooctyl.

Cycloalkoxy represents, in the context of the invention, an alkoxyradical whose hydrocarbon radical is a cycloalkyl radical. Thecycloalkyl radical generally has up to 8 carbon atoms. Examples whichmay be mentioned are: cyclopropyloxy and cyclohexyloxy. The terms“cycloalkoxy” and “cycloalkyloxy” are used synonymously.

Aryl generally represents an aromatic radical having 6 to 10 carbonatoms. Preferred aryl radicals are phenyl and naphthyl.

Halogen represents, in the context of the invention, fluorine, chlorine,bromine and iodine.

Heterocycle generally represents, in the context of the invention, asaturated, unsaturated or aromatic 3- to 10-membered, for example 5- or6-membered, heterocycle which may contain up to 3 heteroatoms from thegroup consisting of S, N and O and which, in the case of a nitrogenatom, may also be attached via this nitrogen atom. Examples which may bementioned are: oxadiazolyl, thiadiazolyl, pyrazolyl, pyridyl,pyrimidinyl, pyridazinyl, pyrazinyl, thienyl, furyl, pyrrolyl,pyrrolidinyl, piperazinyl, tetrahydropyranyl, tetrahydrofuranyl,1,2,3-triazolyl, thiazolyl, oxazolyl, imidazolyl, morpholinyl orpiperidyl. Preference is given to thiazolyl, furyl, oxazolyl, pyrazolyl,triazolyl, pyridyl, pyrimidinyl, pyridazinyl and tetrahydropyranyl. Theterm “heteroaryl” (or “hetaryl”) represents an aromatic heterocyclicradical.

In the heterocycle structures shown in the present application, in eachcase only one bond to the adjacent group is indicated, for example inthe heterocycle structures suitable for Y the bond to the unit Q.However, as indicated, these heterocycle structures may, independentlyof this, carry further substituents.

The present invention furthermore relates to a process for preparingcompounds of the formula (I), characterized in that

-   -   [A] compounds of the formula (II)    -   are reacted with compounds of the formula (III)        E-X—R¹   (III)        -   in which        -   R¹, R², R³, V, Q, Y, W, X, U, A and m are as defined above,        -   E is either a leaving group which is substituted in the            presence of a base or is an optionally activated hydroxyl            function;    -   or    -   [B] compounds of the formula (IV)    -   are reacted with compounds of the formula (V)        -   in which        -   R¹, R², R³, V, Q, Y, W, X, U, A and m are as defined above,        -   E is either a leaving group which is substituted in the            presence of a base or is an optionally activated hydroxyl            function;    -   or    -   [C] compounds of the formula (VI)    -   are reacted with compounds of the formula (VII)        E-U-A-R²   (VII)        -   in which        -   R¹, R², R³, V, Q, Y, W, X, U, A and mare as defined above,        -   E is either a leaving group which is substituted in the            presence of a base or is an optionally activated hydroxyl            function,    -   or    -   [D] compounds of the formula (VIII),        -   in which        -   Va is O or S and        -   R¹, R², R³, Y, Q, W, U, A, X and m are as defined in Claim            3,    -   are reacted with compounds of the formula (IX)        -   in which        -   Q, Y are as defined above,        -   E is either a leaving group which is substituted in the            presence of a base or is an optionally activated hydroxyl            function;    -   or    -   [E] compounds of the formula (X)        -   in which        -   R³, V, Q, Y, W, X, U, A and m are as defined above,        -   R¹ _(b) and R² _(b) independently each represent CN or            COOAlk, where Alk represents a straight-chain or branched            alkyl radical having up to 6 carbon atoms,    -   are converted with aqueous solutions of strong acids or strong        bases into the corresponding free carboxylic acids;    -   or    -   [F] compounds of the formula (XI)        -   in which        -   R¹, R², R³, V, Q, X, W, U, A and m are as defined above,        -   L represents Br, I or the group CF₃SO₂—O,    -   are reacted with compounds of the formula (XII)        M-Z   (XII)        -   in which        -   M represents an aryl or heteroaryl radical, a straight-chain            or branched alkyl, alkenyl or alkinyl radical or cycloalkyl            radical or represents an arylalkyl, an arylalkenyl or an            arylalkinyl radical,        -   Z represents the groupings —B(OH)₂, —CH≡CH, —CH═CH₂ or            —Sn(nBu)₃,    -   in the presence of a palladium compound, if appropriate        additionally in the presence of a reducing agent and further        additives and in the presence of a base;    -   or    -   [G] compounds of the formula (XIII)        -   in which        -   Ar represents an aryl or heteroaryl radical,        -   E is a leaving group which is substituted in the presence of            a base,    -   are reacted according to process D with compounds of the        formula (VIII) and the resulting compounds of the formula (XIV)    -   are hydrogenated with hydrogen in the presence of a catalyst.

The processes according to the invention for preparing compounds of theformula (I) are illustrated below using exemplary, non-limitingembodiments:

Example of the Reaction Sequence According to Processes A/E:

If (VIII) represents, for example, methyl4-{[(2-methoxyphenethyl)amino]-methyl}benzoate and (IX) represents2-chlorophenylmethyl chloride, processes D and E can be represented asshown in the scheme below:

Example of the Reaction Sequence According to Processes D/E:

If (IV) represents, for example, methyl4-{[(5-methoxy-5-oxypentyl)amino]-methyl}benzoate and (V) represents1-[2-(benzyloxy)phenyl]-2-bromo-1-ethanone, processes B and E can berepresented as shown in the scheme below:

Example of the Reaction Sequence According to Processes B/E:

If (VI) represents, for example, methyl5-{[2-(benzyloxy)-phenethyl]amino}pentanoate and (VII) represents methyl4-(bromomethyl)-benzoate, processes C and E can be represented as shownin the scheme below:

Example of the Reaction Sequence According to Processes C/E:

Example of the Reaction Sequence According to Processes D/F/E

Example of the Reaction Sequence According to Processes D/G/E

The solvents which are preferred for the processes according to theinvention are customary organic solvents which do not change under thereaction conditions, or water. Preference may be given to using, for theprocesses according to the invention, ethers, such as diethyl ether,butyl methyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether ordiethylene glycol dimethyl ether, or hydrocarbons, such as benzene,toluene, xylene or petroleum ether, or amides, such as dimethylformamideor hexamethylphosphoric triamide, or 1,3-dimethyl-imidazolidin-2-one,1,3-dimethyl-tetrahydropyrimidin-2-one, acetonitrile, ethyl acetate ordimethyl sulphoxide. It is, of course, also possible to use mixtures ofthe abovementioned solvents.

The bases which are preferred for the processes according to theinvention include basic compounds which are customarily used for basicreactions. Preference may be given to using alkali metal hydrides, suchas, for example, sodium hydride or potassium hydride, or alkali metalalkoxides, such as sodium methoxide, sodium ethoxide, potassiummethoxide, potassium ethoxide or potassium t-butoxide, or carbonates,such as sodium carbonate, caesium carbonate or potassium carbonate, or.amides, such as sodium amide or lithium diisopropylamide, ororganolithium compounds, such as phenyllithium, butyllithium ormethyllithium, or sodium hexamethyldisilazane.

The processes A to C according to the invention can preferably becarried out in acetonitrile, in each case by reacting the compounds (II)and (III), (IV) and (V) and (VI) and (VII), respectively, in thepresence of a base, such as sodium carbonate, Et₃N, DABCO, K₂CO₃, KOH,NaOH or NaH. The reaction can generally be carried out in a temperaturerange of from −20° C. to +90° C., preferably from 0° C. to +70° C. Thereaction can be carried out at atmospheric pressure, elevated or reducedpressure (for example in a range of from 0.5 to 5 bar). In general, thereaction is carried out at atmospheric pressure.

In the processes A to C according to the invention, a compound of theformula (I) is prepared by nucleophilic substitution of a leaving groupE in one of the compounds of the formula (III), (V) or (VII) by theamine function of one of the compounds of the formula (II), (IV) or(VI). Suitable leaving groups E are, for example: halogen, tosylate,mesylate, or a hydroxyl function which is activated by reagents such asdiisopropyl azodicarboxylate/PPh₃ (Mitsonobu reaction).

The process D according to the invention can preferably be carried outin acetonitrile by reacting the compounds (VIII) and (IX) in thepresence of a base, such as sodium carbonate, potassium carbonate, Et₃N,DABCO, K₂CO₃, KOH, NaOH or NaH. The reaction can generally be carriedout in a temperature range of from −20° C. to +90° C., preferably from0C to +90° C. The reaction can be carried out at atmospheric pressure,elevated or reduced pressure (for example in a range of from 0.5 to 5bar). In general, the reaction is carried out at atmospheric pressure.

In the process D according to the invention, a compound of the formula(I) is prepared by nucleophilic substitution of a leaving group E in thecompound of the formula (IX) by the hydroxyl or thiol function of thecompound of the formula (VIII). Suitable leaving groups E are, forexample: halogen, tosylate, mesylate, or a hydroxyl function which isactivated by reagents such as diisopropyl azodicarboxylate/PPh₃(Mitsonobu reaction).

In the process E according to the invention, a compound of the formula(I), where R¹ and R² each represent a free carboxyl function, isobtained by converting ester and/or nitrile functions of the compound(X) into the corresponding free carboxyl functions. This reaction can becarried out, for example, by adding aqueous solutions of strong acids,such as, for example, HCl or H₂SO₄, or strong bases, such as, forexample, NaOH, KOH or LiOH. The reaction can be carried out in one ofthe abovementioned organic solvents, in water or in mixtures of organicsolvents or in mixtures of organic solvents with water. Preferenceaccording to the invention is given, for example, to carrying out thereaction in a mixture of water and methanol or dioxane. The reaction cangenerally be carried out in a temperature range of from −20° C. to +90°C., preferably from 0° C. to +90° C. The reaction can be carried out atatmospheric pressure, elevated or reduced pressure (for example in arange of from 0.5 to 5 bar). In general, the reaction is carried out atatmospheric pressure.

In the process F according to the invention, a compound of the formula(I) is prepared by reacting a compound of the formula (XI), whichcontains a substitutable group L, with a compound of the group (XII) inthe presence of a palladium compound and, if appropriate, a reducingagent and further additives in basic medium. Formally, the reaction is areductive coupling of the compounds of the formulae (XI) and (XII), asdescribed, for example, in L. S. Hegedus, Organometallics in Synthesis,M. Schlosser, Ed., Wiley & Sons, 1994.

In the compounds of the formula (XI), the substitutable group L can, forexample, be a halogen radical, such as Br or I, or a customary leavinggroup, such as, for example, a triflate radical.

The compounds of the formula (XII) contain a reactive group Z which canbe selected from the group consisting of —B(OH)₂, —CH═CH, —CH═CH₂ or—Sn(nBu)₃.

The palladium compound used can be a palladium (II) compound, such as,for example, Cl₂Pd(PPh₃)₂ or Pd(OAc)₂, or a palladium (0) compound, suchas, for example, Pd(PPh₃)₄ or Pd₂(dba)₃. If required, it is possible toadd additionally a reducing agent, such as, for example,triphenylphosphine, or other additives, such as, for example, Cu(I)Br,NBu₄NCl, LiCl or Ag₃PO₄, to the reaction mixture (cf. T. Jeffery,Tetrahedron Lett. 1985, 26, 2667-2670; T. Jeffery, J. Chem. Soc., Chem.Commun. 1984, 1287-1289; S. Bräse, A. deMejiere in “Metal-catalyzedcross-coupling reactions”, Ed. F. Diederich, P. J. Stang, Wiley-VCH,Weinheim 1998, 99-166).

The reaction is carried out in the presence of a customary base, suchas, for example, Na₂CO₃, NaOH or triethylamine. Suitable solvents arethe organic solvents mentioned above, and particular preference is givento ethers, such as, for example, dimethoxyethane. The reaction can, ingeneral, be carried out in a temperature range of from −20° C. to +90°C., preferably from 0° C. to +90° C. The reaction can be carried out atatmospheric pressure, elevated or reduced pressure (for example in arange of from 0.5 to 5 bar). In general, the reaction is carried out atatmospheric pressure.

In the process G according to the invention, compounds of the formula(I) are obtained by reacting compounds of the formula (XIII), whichcontain a leaving group E, with compounds of the formula (VIII)according to the process D according to the invention, followed byhydrogenation of the resulting compounds of the formula (XIV).

Thus, the first step of the process G proceeds analogously to theprocess D, but instead of the compounds of the formula (IX), compoundsof the formula (XIII) are reacted here with the alcohols or thiols ofthe formula (XIII). This gives the unsaturated compounds of the formula(XIV), which can be converted by customary hydrogenation processes intothe compounds of the formula (I).

Preference according to the invention is given to the hydrogenation ofcompounds of the formula (XIV) with hydrogen in the presence of acatalyst, such as, for example, Pd/carbon or PtO.

The process G can be carried out in one of the abovementioned organicsolvents. Preference is given here to ethyl acetate. In general, thereaction can be carried out in a temperature range of from −20° C. to+90° C., preferably from 0° C. to +90° C. The reaction can be carriedout at atmospheric pressure, elevated or reduced pressure (for examplein a range of from 0.5 to 5 bar). In general, the reaction is carriedout at atmospheric pressure.

The amines of the formulae II, IV and VI are novel and also form part ofthe subject-matter of the invention.

The novel compounds of the formulae II, IV and VI can be obtained in agenerally known manner by the following methods:

a) by reacting amines of the formulae (XV), (XVI) and (XVII)

-   -   where the radicals R¹, R², R³, m, V, Q, U, W, X, Y and A are as        defined above;

with carbonyl compounds of the formulae (XVIII), (XIX), (XX)

-   -   where    -   Ua, Wa and Xa have the meanings of U, W and X, respectively, but        are one carbon unit shorter, and    -   T represents hydrogen or a C₁-C₄-alkyl function, which can also        be attached to Ua or Xa to form a cycle,    -   and the other radicals are as defined above,

initially to give a Schiff base which is then reduced with customaryreducing agents, such as, for example, NaBH₄, H₂/Pd/C, etc., orconverted directly under the conditions of a reductive alkylation in thepresence of a reducing agent, such as, for example, H₂/Pd/C, NaCNBH₃,NaH(OAc)₃ (cf. Patai, Ed., The Chemistry of the Carbon-Nitrogen DoubleBond, pp. ²76-293 and literature cited therein);

b) by reacting amines of the formulae (XV), (XVI) and (XVII) withcompounds of the formulae (III), (V), (VII) (cf., for example, J. March,Advanced Organic Chemistry, fourth Edition, Wiley, 1992, page 411 andthe literature cited therein).

Amines of the formula (IIa) and compounds of the formula (VIII),

-   -   where Va represents O or S

can be obtained in a generally known manner by the following reactionscheme:

In the above scheme, PGo represents a customary phenol or thiophenolprotective group, such as, for example, CH₃, CH₂Ph, CH₂CH═CH₂, CH₂OCH₃,CH₂OCH₂SiMe₃, SiMe₃, PGn represents an amine protective group, such as,for example, tBuOCO, T represents hydrogen or a C₁-C₄-alkyl functionwhich can also be attached to Ua to form a cycle, and Ua has the meaningof U but is one CH₂ group shorter. The other radicals are as definedabove.

(IIb) is obtained, for example, by initially reacting (XVa) with (XVIII)to give a Schiff base which is then reduced with customary reducingagents, such as, for example, NaBH₄, H₂/Pd/C, etc., or directly reactedunder the conditions of a reductive alkylation in the presence of areducing agent, such as, for example, H₂/Pd/C, NaCNBH₃ or NaH(OAc)₃. Thecompound (IIb) can be converted by reaction with a compound of theformula (III) in the presence of a base into a compound of the formula(XXI) (cf. process A).

An O— or S-protective group in (IIb) or (XXI) can be eliminated using asuitable reagent (cf. T. W. Greene, P. G. M. Wuts, Protective Groups inOrganic Synthesis, second edition, New York, 1991). If, for example, informula (IIb) or (XXI)-Va-PGo represents —O—CH₃, the methyl group can beeliminated with formation of the phenol using boron tribromide inmethylene chloride at from −70 to 20° C., using trimethylsilyl iodide inchloroform at 25-50° C. or using sodium ethylthiolate in DMF at 150° C.

From the resulting compound of the formula (IIc), a compound of theformula (XXIII) can be obtained by protecting the amino function (cf. T.W. Greene, P. G. M. Wuts, Protective Groups in Organic Synthesis, secondedition, New York, 1991) and subsequent reaction of the resultingamine-protected compound of the formula (XXII) with a compound of theformula (IX) (cf. process D).

An N-protective group such as in (XXII) can be introduced and removedagain by customary methods (cf. T. W. Greene, P. G. M. Wuts, ProtectiveGroups in Organic Synthesis, second edition, New York, 1991). If PGn inthe formula (XXII) represents, for example, tBuOCO, the protective groupcan be introduced by reacting the amine with tert-butyl pyrocarbonate inpolar or nonpolar solvents at from 0° C. to 25° C. Removal of theprotective group to (IIa) can be carried out with numerous acids, suchas, for example, HCl, H₂SO₄ or CF₃COOH, at from 0° to 25° C. (cf. theliterature cited above).

Substances of the formula (III) are commercially available, known fromthe literature or synthesizable by processes known from the literature(cf. for example, J. Chem. Soc. 1958, 3065).

Substances of the formula (V) are known from the literature orsynthesizable analogously to processes known from the literature (cf.,for example, J. Med. Chem. 1989, 32, 1757; Indian J. Chem. Sect. B 1985,24, 1015; Recl. Trav. Chim. Pays-Bas 1973, 92, 1281; Tetrahedron Lett.1986, 37, 4327).

Substances of the formula (VII) are commercially available, known fromthe literature or synthesizable analogously to processes known from theliterature (cf., for example, J. Org. Chem. 1959, 24, 1952; CollectCzech. Chem. Commun 1974, 39, 3527; Helv. Chim. Acta 1975, 58, 682;Liebigs Ann. Chem. 1981, 623).

Substances of the formula (IX) are commercially available, known fromthe literature or synthesizable analogously to processes known from theliterature (cf., for example, J. prakt. Chem. 1960, 341; Farmaco Ed.Sci. 1956, 378; Eur. J. Med. Chem. Chim. Ther. 1984, 19, 205; Bull. Soc.Chim. Fr. 1951, 97. Liebigs Ann. Chem. 1954, 586, 52; EP-A-0 334 137).In particular, 4-chloromethylbiphenyl compounds which carry a furthersubstituent in the 4′-position can be prepared by coupling4-(B(OH)₂—Ph—CHO with the corresponding 4-substituted bromophenylcompounds in the presence of palladium catalysts, such as, for example,Pd(PPh₃)₄ or PdCl₂(PPh₃)₂ and sodium carbonate to give the correspondingbiphenyl compounds, followed by reduction to give the alcohol usingNaBH₄ and conversion into the corresponding chloride using, for example,SOCl₂.

If E in the formulae (III), (V), (VII) and (IX) represents halogen, thecompounds can also be prepared by generally known processes, for exampleby reaction of an alcohol with a chlorinating agent, such as, forexample, thionyl chloride or sulphuryl chloride, (cf., for example, J.March, Advanced Organic Chemistry, fourth Edition, Wiley, 1992, page1274 and the literature cited therein).

Amines of the formula (XV) are commercially available, known from theliterature or synthesizable analogously to processes known from theliterature (cf., for example, Tetrahedron 1997, 53, 2075; J. Med. Chem.1984, 27, 1321; WO97/29079; J. Org. Chem. 1982, 47, 5396). Thesecompounds can be obtained, for example, from the corresponding halidecompounds and in particular chloride compounds where, instead of theradicals W—NH₂ of the compounds of the formula (XV), a group W′-Hal ispresent in which W′ is a radical W which is shortened by one C atom, bysubstitution of the halide radical by a cyano group, giving thecorresponding nitrile compounds, and reduction of the nitrile group, orby reaction of the corresponding aldehyde compounds in which, instead ofthe radicals W—NH₂ of the compounds of the formula (XV), a group W′—CHOis present where W′ is a radical W which is shortened by one C atom,with nitromethane, and subsequent reduction.

Amines of the formula (XVI) are commercially available, known from theliterature or synthesizable analogously to processes known from theliterature (cf., for example, J. Am. Chem. Soc. 1982, 104, 6801; Chem.Lett. 1984, 1733; J. Med. Chem. 1998, 41, 5219; DE-2059922).

Amines of the formula (XVII) are commercially available, known from theliterature or synthesizable analogously to processes known from theliterature (cf., for example, J. Org. Chem. 1968, 33, 1581; Bull. Chem.Soc. Jpn. 1973, 46, 968; J. Am. Chem. Soc. 1958, 80, 1510; J. Org. Chem.1961, 26, 2507; Synth. Commun. 1989, 19, 1787).

Amines of the formulae (XV), (XVI) and (XVII) can also be prepared bygenerally known processes, for example by reduction of a correspondingnitrile, by reacting a corresponding halide with phthalimide andsubsequent reaction with hydrazine or by the rearrangement of acylazides in the presence of water (cf., for example, J. March, AdvancedOrganic Chemistry, fourth Edition, Wiley, 1992, page 1276 and theliterature cited therein).

Carbonyl compounds of the formula (XVIII) are commercially available,known from the literature or synthesizable analogously to processesknown from the literature (cf., for example, J. Med. Chem. 1989, 32,1277; Chem. Ber. 1938, 71, 335; Bull. Soc. Chim. Fr. 1996, 123, 679).

Carbonyl compounds of the formula (XIX) are commercially available,known from the literature or synthesizable analogously to processesknown from the literature (cf., for example, WO96/11902; DE-2209128;Synthesis 1995, 1135; Bull. Chem. Soc. Jpn. 1985, 58, 2192).

Carbonyl compounds of the formula (XX) are commercially available, knownfrom the literature or synthesizable analogously to processes known fromthe literature (cf., for example, Synthesis 1983, 942; J. Am. Chem. Soc.1992, 114, 8158).

Carbonyl compounds of the formulae (XVIII), (XIX) and (XX) can also beprepared by generally known processes, for example by oxidation ofalcohols, reduction of acyl chlorides or reduction of nitrites (cf., forexample, J. March, Advanced Organic Chemistry, fourth Edition, Wiley,1992, page 1270 and the literature cited therein).

Compounds of the formula (XII) are commercially available, known fromthe literature or synthesizable analogously to processes known from theliterature (cf., for example, for aromatic boronic acids: J. Chem. Soc.C 1966, 566. J. Org. Chem., 38, 1973, 4016; or for tributyltincompounds: Tetrahedron Lett. 31, 1990, 1347).

Compounds of the formula (XIII) are commercially available, known fromthe literature or synthesizable analogously to processes known from theliterature (cf., for example, J. Chem. Soc. Chem. Commun., 17, 1994,1919).

The compounds according to the invention, in particular the compounds ofthe general formula (I), have an unforeseeable useful pharmacologicalactivity spectrum.

The compounds according to the invention, in particular the compounds ofthe general formula (I), effect a relaxation of the vessels, inhibitplatelet aggregation and lower the blood pressure, and also increasecoronary blood flow. These effects are mediated via direct stimulationof soluble guanylate cyclase and intracellular cGMP increase.

They can therefore be employed in medicaments for the treatment ofcardiovascular disorders, such as, for example, for the treatment ofhypertension and cardiac insufficiency, stable and unstable anginapectoris, peripheral and cardiac vascular disorders, arrhythmias, forthe treatment of thromboembolic disorders and ischaemias, such asmyocardial infarct, stroke, transitory and ischaemic attacks, peripheralcirculatory disorders, prevention of restenoses such as afterthrombolysis therapy, percutaneous transluminal angioplasty (PTA),percutaneous transluminal coronary angioplasty (PTCA), bypass and alsofor the treatment of arteriosclerosis, fibrotic disorders, such ashepatic fibrosis or pulmonary fibrosis, asthmatic disorders anddisorders of the urogenital system, such as, for example, prostatehypertrophy, erectile dysfunction, female sexual dysfunction andincontinence, and also for the treatment of glaucoma.

The compounds described in the present invention, in particular thecompounds of the general formula (I), are also active compounds forcontrolling disorders in the central nervous system which arecharacterized by disturbances of the NO/cGMP system. In particular, theyare suitable for eliminating cognitive deficits, for improving learningand memory performance and for treating Alzheimer's disease. They arealso suitable for the treatment of disorders of the central nervoussystem, such as states of anxiety, tension and depression, sleepingdisorders and sexual dysfunction caused by the central nervous system,and for regulating pathological eating disorders or disorders associatedwith the use of stimulants and drugs.

Furthermore, the active compounds are also suitable for regulatingcerebral circulation, and they are therefore effective agents forcontrolling migraine.

They are also suitable for the prophylaxis and control of sequelae ofcerebral infarct (Apoplexia cerebri) such as stroke, cerebral ischaemiasand skull-brain trauma. The compounds according to the invention, inparticular the compounds of the general formula (I), can also beemployed for controlling pain.

Additionally, the compounds according to the invention haveantiinflammatory action and can therefore be employed asantiinflammatories.

Vasal Relaxant Action in vitro

Rabbits are anaesthetized by intravenous injection of thiopental sodiumor killed (about 50 mg/kg) and exsanguinated. The arteria saphena isremoved and divided into 3 mm wide rings. The rings are individuallymounted on in each case one triangular pair of hooks, open at the end,made of 0.3 mm strong special wire (Remanium®). Under a pretension, eachring is transferred into 5 ml organ baths containing a warm,carbogen-aerated Krebs-Henseleit solution at 37° C. having the followingcomposition (mM): NaCl: 119; KCl: 4.8; CaCl₂×2 H₂O: 1; MgSO₄×7 H₂O: 1.4;KH₂PO₄: 1.2; NaHCO₃: 25; glucose: 10; bovine serum albumin: 0.001%. Thecontractility is detected using Statham UC2 cells, amplified anddigitalized by means of A/D converters (DAS-1802 HC, KeithleyInstruments Munich), and recorded in parallel on linear recorders.Contractions are induced by addition of phenylephrin.

After several (in general 4) control cycles, the substance to beinvestigated is added in each further passage in increasing dosage, andthe height of the contraction acheived under the influence of the testsubstance is compared with the height of the contraction achieved in thelast preliminary passage. From this, the concentration which isnecessary in order to reduce the contraction achieved in the preliminarycontrol by 50% ((IC₅₀) is calculated. The standard administration volumeis 5 μl. The proportion of DMSO in the bath solution corresponds to0.1%.

The results are shown in Table 1: TABLE 1 vasorelaxant action in vitroExample IC₅₀ (nM) 8 0.4 28 2.8 30 17 32 6.5 33 0.5 37 830 56 73 70 0.272 29 76 29 86 0.4 87 0.5 88 0.4 98 3.4 102 0.2 103 3.9 186 0.90

Stimulation of Recombinant Soluble Guanylate Cyclase (sGC) in vitro

The investigations on the stimulation of recombinant soluble guanylatecyclase (sGC) and the compounds according to the invention with andwithout sodium nitroprusside and with and without the haem-dependent sGCinhibitor 1H-1,2,4-oxadiazole-(4,3a)-quinoxalin-1-one (ODQ) were carriedout by the method described in detail in the following literaturereference: M. Hoenicka, E. M. Becker, H. Apeler, T. Sirichoke, H.Schroeder, R. Gerzer and J.-P. Stasch: Purified soluble guanylyl cyclaseexpressed in a baculovirus/Sf9 system: stimulation by YC-1, nitricoxide, and carbon oxide. J. Mol. Med. 77 (1999): 14-23.

Haem-free guanylate cyclase was obtained by adding Tween 20 to thesample buffer (final concentation 0.5%).

Activation of sGC by a test substance is stated as n-fold stimulation ofbasal activity.

The results are shown in Table 2. TABLE 2 Stimulation of recombinantsoluble guanylate cyclase (sGC) in vitro Stimulation (n-fold) Ex. 87Haem-containing sGC Haem-free sGC concentration + SNP + ODQ + ODQ (μM)basal (0.1 μM) (10 μM) basal (10 μM) 0 1 15 1 1 1 0.1 15 41 132 353 3611.0 18 47 115 491 457 10 24 60 181 529 477

It can be seen from Table 2 that stimulation both of the haem-containingand of the haem-free enzyme is achieved. Furthermore, a combination ofsGC stimulator and sodium nitroprusside (SNP), an NO donor, does notshow any synergistic effect, i.e. the effect of SNP is not potentiated,as would be expected for an sGC stimulator acting via a haem-dependentmechanism. In addition, the effect of the sGC stimulator according tothe invention is not blocked by the haem-dependent inhibitor of solubleguanylate cyclase, ODQ. Thus, the results in Table 2 demonstrate thenovel mechanism of action of the stimulators according to the inventionof soluble guanylate cyclase.

The present invention includes pharmaceutical preparations which, inaddition to non-toxic, inert, pharmaceutically acceptable excipients,contain the compounds according to the invention, in particular thecompounds of the general formula (I), and also processes for theproduction of these preparations.

The active compounds can optionally be present in one or more of theexcipients indicated above and also in microencapsulated form.

The therapeutically active compounds, in particular the compounds of thegeneral formula (I), should be present in the abovementionedpharmaceutical preparations in a concentration from approximately 0.1 to99.5, preferably from approximately 0.5 to 95, % by weight of the totalmix.

In addition to the compounds according to the invention, in particularthe compounds of the general formula (I), the abovementionedpharmaceutical preparations can also contain other pharmaceuticallyactive compounds.

In general, it has proved advantageous both in human and in veterinarymedicine to administer the active compound(s) according to the inventionin total amounts of from approximately 0.5 to approximately 500,preferably 5 to 100, mg/kg of bodyweight every 24 hours, if appropriatein the form of several individual doses, to achieve the desired results.An individual dose contains the active compound(s) according to theinvention preferably in amounts from approximately 1 to approximately80, in particular 3 to 30, mg/kg of bodyweight.

Below, the present invention is illustrated in more detail usingnon-limiting, preferred examples. Unless indicated otherwise, allamounts given refer to percent by weight.

EXAMPLES

Abbreviations:

-   RT: Room temperature-   EA: Ethyl acetate-   BABA: n-Butyl acetate/n-butanol/glacial acetic acid/phosphate buffer    pH 6 (50:9:25.15; org. phase)

Mobile Phases for Thin-Layer Chromatograhy:

-   T1 E1: Toluene/ethyl acetate (1:1)-   T1 EtOH1: Toluene/methanol (1:1)-   C1 E1: Cyclohexane/ethyl acetate (1:1)-   C1 E2: Cyclohexane/ethyl acetate (1:2)

Starting Materials

Examples I-IV) Compounds of the Formula VIII I.1. Methyl4-{[(2-methoxyphenethyl)amino]methyl}benzoate

A solution of 9.23 g (56.16 mmol) of 2-methoxyphenethylamine and 9.219 g(56.16 mmol) of methyl 4-formylbenzoate in 35 ml of ethanol is heated atreflux for two hours. The solvent is distilled off under reducedpressure, giving 17.5 g of the imine which is reacted further withoutfurther purification.

17.5 g (58.85 mmol) of the imine are dissolved in 200 ml of methanoland, a little at a time, admixed with 4.45 g (117.7 mmol) of sodiumborohydride. The reaction mixture is stirred at room temperature for twohours and then poured into water and extracted with ethyl acetate, andthe organic phases are washed with saturated sodium chloride solutionand dried. Distillative removal of the solvent under reduced pressuregives the product as an oil.

Yield: 16.04 g (91% of theory).

¹H-NMR (200 MHz, d⁶-DMSO): δ=2.70 (m, 4H), 3.80 (s, 3H), 3.85 (s, 3H),6.90 (m, 2H), 7.15 (m, 2H), 7.45 (d, 2H), 7.90 (s, 2H).

I.2. Methyl4-{[(5-ethoxy-5-oxopentyl)(2-methoxyphenethyl)amino]methyl}benzoate

15.0 g (50.0 mmol) of methyl4-{[(2-methoxyphenethyl)amino]methyl}benzoate from Example I.1., 11.52 g(55.0 mmol) of ethyl 5-bromovalerate and 6.37 g (106.0 mmol) of sodiumcarbonate are dissolved in 30 ml of acetonitrile and heated at refluxfor 18 hours. After cooling, most of the solvent is distilled off underreduced pressure and the residues are mixed with water. The mixture isextracted repeatedly with ethyl acetate, the organic phases are washedwith saturated sodium chloride solution and, after drying over magnesiumsulphate, the solvent is removed under reduced pressure. The crudeproduct is purified by flash chromatography over silica gel (0.04-0.063nm) using the mobile phase cyclohexane/ethyl acetate 4/1.

Yield: 17.77 g (80.4% of theory)

¹H-NMR (200 MHz, d⁶-DMSO): δ=1.13 (t, 3H), 1.45 (m, 4H), 2.20 (t, 2H),2.45 (t, 2H), 2.58 (m, 2H), 2.70 (m, 2H), 3.70 (s, 3H), 3.85 (s, 3H),4.05 (q, 2H), 6.8-6.9 (m, 2H), 7.0-7.2 (m, 2H), 7.40 (d, 2H), 7.86 (d,2H).

Methyl4-{[(2-hydroxyphenethyl)(5-methoxy-5-oxopentyl)amino]methyl}benzoate

A solution of 3.00 g (7.02 mmol) of methyl4-{[(5-ethoxy-5-oxopentyl)(2-methoxy-phenethyl)amino]methyl}benzoatefrom Example I.2 in 60 ml of methylene chloride is cooled to 0° C., and23.16 ml (23.16 mmol) of a 1N boron tribromide solution in methylenechloride are added dropwise. The solution is stirred at 0° C. for onehour. After addition of 30 ml of dry methanol, the batch is heated at60° C. for one hour. After cooling, the solvent is removed under reducedpressure and the residue is taken up in a mixture of 57 ml of ethylacetate and 3 ml of methanol and made alkaline using 10% sodiumcarbonate solution. The aqueous phase is extracted repeatedly with ethylacetate/methanol 9/1 and the combined organic phases are washed usingsaturated sodium chloride solution. After drying over magnesium sulphateand distillative removal of the solvent under reduced pressure, thecrude product is purified by flash chromatography over silica gel(0.04-0.063 nm) using the mobile phase cyclohexane/ethyl acetate 2/1.

Yield: 1.89 g (64.2% of theory)

¹H-NMR (200 MHz, d⁶-DMSO): δ=1.46 (m, 4H), 2.23 (t, 2H), 2.45 (t, 2H),2.60 (m, 2H), 2.70 (m, 2H), 3.60 (s, 3H), 3.70 (s, 2H), 3.85 (s, 3H),6.70 (m, 2H), 7.01 (m, 2H), 7.45 (d, 2H), 7.90 (d, 2H), 9.50 (s, 1H).

The following compounds were obtained in the same manner:

II. Methyl4-{[(5-ethoxy-5-oxopentyl)(2-hydroxybenzyl)amino]methyl}benzoate

This compound can be obtained analogously to Example I starting from2-methoxybenzylamine instead of 2-methoxyphenethylamine.

¹H-NMR (200 MHz, d⁶-DMSO): δ=1.15 (t, 3H), 1.50 (m, 4H), 2.15 (m, 2H),2.40 (m, 2H), 3.65 (s, 4H), 3.85 (s, 3H), 4.01 (q, 2H), 6.75 (t, 2H),7.0-7.2 (m, 2H), 7.45 (d, 2H), 7.94 (d, 2H), 10.0 (br. s, 1H)

III. Methyl4-{[(5-ethoxy-5-oxopentyl)(3-hydroxyphenethyl)amino]methyl}benzoate

This compound can be obtained analogously to Example I starting from3-methoxyphenethylamine instead of 2-methoxyphenethylamine.

¹H-NMR (200 MHz, d⁶-DMSO): δ=1.46 (m, 4H), 2.23 (t, 2H), 2.45 (t, 2H),2.60 (m, 2H), 2.70 (m, 2H), 3.60 (s, 3H), 3.70 (s, 2H), 3.85 (s, 3H),6.70 (m, 2H), 7.01 (m, 2H), 7.45 (d, 2H), 7.90 (d, 2H), 9.50 (s, 1H).

IV. Methyl3-{[(5-ethoxy-5-oxopentyl)(2-hydroxyphenethyl)amino]methyl}benzoate

This compound can be obtained analogously to Example I starting frommethyl 3-formylbenzoate instead of methyl 4-formylbenzoate.

¹H-NMR (200 MHz, d⁶-DMSO): δ=1.48 (m, 4H), 2.21(t, 2H), 2.47 (t, 2H),2.64 (m, 2H), 2.71 (m, 2H), 3.60 (s, 3H), 3.70 (s, 2H), 3.85 (s, 3H),6.70 (m, 2H), 7.0-7.7 (d, 8H), 9.50 (s, 1H).

Examples V-VIII) Compounds of the Formula II V.1. Methyl4-{[(2-hydroxyphenethyl)amino]methyl}benzoate

At 0° C, 176.8 ml (176.8 mmol) of a 1N boron tribromide solution inmethylene chloride are added dropwise to 16.03 g (53.561 mmol) of methyl4-{[(2-methoxyphenethyl)amino]methyl}benzoate from Example. I.1 in 100ml of methylene chloride. After one hour of stirring at 0° C., 150 ml ofmethanol are added and the solution is heated at reflux for 4 hours. Thesolvent is distilled off under reduced pressure and the residue is takenup in a mixture of 190 ml of ethyl acetate and 10 ml of methanol. Using10% strength sodium carbonate solution, the mixture is made alkaline andextracted with ethyl acetate/methanol 9/1. The combined organic phasesare washed with saturated sodium chloride solution and dried overmagnesium sulphate, and the solvent is distilled off under reducedpressure. The crude product is purified by chromatography over silicagel (0.04-0.063 nm) using the mobile phase methylene chloride/methanol100/2.

Yield: 6.80 g (42.9% of theory)

¹H-NMR (200 MHz, d⁶-DMSO): δ=2.73 (s, 4H), 3.82 (s, 2H), 3.85 (s, 3H),6.7 (m, 2H), 7.0 (d, 2H), 7.48 (d, 2H), 7.92 (d, 2H).

V.2. Methyl4-{[(tert-butoxycarbonyl)(2-hydroxyphenethyl)amino]methyl}-benzoate

6.80 g (23.82 mmol) of methyl4-{[(2-methoxyphenethyl)amino]methyl}benzoate from Ex. V.1. areinitially charged in 25 ml of methylene chloride and a solution of 5.46g (25.02 mmol) of tert-butyl pyrocarbonate in 25 ml of methylenechloride is added dropwise at 0° C. After 18 hours of stirring at 22°C., the solvent is distilled off under reduced pressure.

Yield: 9.56 g (99% of theory)

¹H-NMR (200 MHz, d⁶-DMSO): δ=1.32 (s, 9H), 2.70 (t, 2H), 3.35 (m, 2H),3.83 (s, 3H), 4.42 (s, 2H), 6.6-6.8 (m, 2H), 7.0 (m, 2H), 7.35 (d, 2H),7.92 (d, 2H).

V.3. Methyl4[((tert-butoxycarbonyl){2-[(5-phenylpentyl)oxy]-phenethyl}amino)-methyl]benzoate

1.78 g (4.63 mmol) of methyl4-{[(tert-butoxycarbonyl)-(2-hydroxyphenethyl)-amino]methyl}benzoatefrom Ex.V.2, 1.05 g (4.63 mmol) of 5-phenyl-1-bromopentane and 0.77 g(5.55 mmol) of potassium carbonate in 15 ml of acetonitrile are heatedat reflux for 18 hours. The reaction mixture is poured into water,extracted with ethyl acetate and dried over magnesium sulphate and thesolvent is distilled off under reduced pressure. A solid is obtainedwhich is reacted further without purification.

Yield: 2.42 g (88.8% of theory)

¹H-NMR (200 MHz, d⁶-DMSO): δ=1.32 (s, 9H), 1.55 (m, 4H), 1.65 (m, 2H),2.70 (m, 2H), 3.36 (m, 2H), 3.79 (s, 3H), 3.90 (t, 2H), 4.40 (s, 2H),6.8-6.9 (m, 2H), 7.1-7.3 (m, 9H), 7.94 (d, 2H)

V.4 Methyl 4-[({2-[(5-phenylpentyl)oxy]phenethyl}amino)methyl]benzoate

2.42 g (4.54 mmol) of methyl4-[((tert-butoxycarbonyl){2-[(5-phenylpentyl)oxy]-phenethyl}amino)methyl]benzoatefrom Ex. V.3 are introduced into a mixture of 4 ml of trifluoroaceticacid and 12 ml of methylene chloride, and the mixture is stirred at 22°C. for 18 hours. The solvent is distilled off completely using a rotaryevaporator, the residue is taken up in water and the product isextracted repeatedly with ethyl acetate. The combined organic phases arewashed twice with 2N aqueous sodium hydroxide solution, dried overmagnesium sulphate and concentrated under reduced pressure.

Yield: 8.25 g (77% of theory)

¹H-NMR (200 MHz, d⁶-DMSO): δ=1.40 (m, 2H), 1.65 (m, 4H), 2.55 (t, 2H),2.70 (m, 2H), 3.80 (s, 3H), 3.84 (s, 3H), 3.90 (t, 2H), 6.8-6.9 (m, 2H),7.1-7.3 (m, 7H), 7.45 (d, 2H), 7.90 (d, 2H)

The following compounds were obtained in the same manner:

VI. Methyl 4-({[2-(heptyloxy)phenethyl]amino}methyl)benzoate

This compound can be obtained analogously to Example V starting fromheptyl bromide instead of 5-phenyl-1-bromopentane.

¹H-NMR (300 MHz, d⁶-DMSO): δ=0.85 (t, 3H), 1.2-1.4 (m, 8H), 1.65 (m,2H), 2.70 (s, 4H), 3.80 (s, 2H), 3.82 (s, 3H), 3.91 (t, 2H), 6.7-6.9 (m,2H), 7.13 (d, 2H), 7.45 (d, 2H), 7.90 (d, 2H).

VII. Methyl4-({[2-([1,1′-biphenyl]-4-ylmethoxy)phenethyl]amino}methyl)benzoate

This compound can be obtained analogously to Example V starting from4-phenylbenzyl bromide instead of 5-phenyl-1-bromopentane.

¹H-NMR (200 MHz, d⁶-DMSO): δ=2.75 (m, 4H), 3.80 (s, 3H), 3.82 (s, 2H),5.13 (s, 2H), 6.7-7.6 (m, 15 H), 7.85 (d, 2H)

VIII. Methyl 4-[({2-[(4-bromobenzyl)oxy]phenethyl}amino)methyl]benzoate

This compound can be obtained analogously to Example V starting from4-bromobenzyl bromide instead of 5-phenyl-1-bromopentane.

¹H-NMR (200 MHz, d⁶-DMSO): δ=2.75 (m, 4H), 3.80 (s, 3H), 3.82 (s, 2H),5.13 (s, 2H), 6.7-7.6 (m, 10 H), 7.85 (d, 2H)

IX. Methyl4-{[{2-[4-(ethoxycarbonyl)phenoxy]ethyl}(2-hydroxyphenethyl)amino]-methylbenzoate

250 mg (0.88 mmol) of methyl4-{[(2-hydroxyphenethyl)amino]methyl}benzoate from Example V.1., 311 mg(1.14 mmol) of ethyl 4-(2-bromoethoxy)benzoate (Eastman Kodak CO,US-279082), and 250 mg (2.37 mmol) of sodium carbonate are dissolved in3 ml of acetonitrile, and the mixture is heated at reflux for 18 hours.After cooling, the solvent is distilled off under reduced pressure andthe residue is purified over silica gel (0.04-0.063 nm) using the mobilephase cyclohexane/ethyl acetate 9/1.

Yield: 274 mg (65.5% of theory)

¹H-NMR (200 MHz, CDCl₃): δ=1.13 (t, 3H), 2.80-3.05 (m, 6H), 3.80-4.35(m, 9H), 6.70-8.00 (m, 12H), 11.40 (bs, 1H).

X: Methyl4-({(5-ethoxy-5-oxopentyl)[2-(2-hydroxyphenyl)ethyl]amino}methyl)-benzoate

This compound was prepared analogously to Ex. IX, except that thealkylating agent used was ethyl bromovalerate instead of ethyl4-(2-bromoethoxy)benzoate.

¹H-NMR (400 MHz, CDCl3): 1.20 (t, 3H), 1.60 (m, 4H), 2.20 (t, 2H), 2.50(m, 2H), 2.80 (m, 4H), 3.80 (s, 2H), 3.90 (s, 3H), 4.10 (q, 2H), 6.70(m, 1H), 6.90 (d, 1H), 6.95 (m, 1H), 7.10 (m, 1H), 7.40 (d, 2H), 8.00(d, 2H), 12.1 (bs, 1H)

XI. Methyl2-bromo-4-({(5-ethoxy-5-oxopentyl)[2-(2-hydroxyphenyl)ethyl]amino}methyl)benzoate

This compound was prepared analogously to Ex. IX, except that thealkylating agent used was ethyl bromovalerate instead of ethyl4-(2-bromoethoxy)benzoate and that the reaction was carried out usingmethyl 2-bromo-4-{[(2-hydroxyphenyl)-ethyl]amino}methyl)benzoate(obtained from 2-methoxyphenethylamine and ethyl3-bromo-4-formylbenzoate analogously to Ex. V.1 [ethyl3-bromo-4-formylbenzoate can be prepared from diethyl2-bromoterephthalate by reduction with 1 eq. of lithium aluminiumchloride and oxidation of the resulting alcohol with manganesedioxide]). ¹H-NMR (200 MHz, CDCl₃): 1.20 (t, 3H), 1.40 (t, 3H), 1.60 (m,4H), 2.20 (t, 2H), 2.50 (m, 2H), 2.80 (m, 4H), 3.80 (s, 2H), 4.10 (q,2H), 4.40 (q, 2H), 6.70 (m, 1H), 6.90 (m, 2H), 7.10 (m, 1H), 7.40 (m,1H), 7.60 (m, 1H), 7.70 (m, 1H), 11.70 (bs, 1H).

XII. Methyl4-({(5-methoxy-5-oxopentyl)[2-(5-fluoro-2-hydroxyphenyl)ethyl]amino}methyl)benzoateXII.1. 5-Fluoro-2-methoxybenzaldehyde

20.0 g (0.143 mol) of 5-fluoro-2-hydroxybenzaldehyde are dissolved in250 ml of acetonitrile. 81.04 g (0.57 mol) of iodomethane and 39.5 g(285 mol) of potassium carbonate are added, and the suspension is heatedat reflux for 3 hours. The suspension is filtered and the mother liquoris diluted with ethyl acetate, washed twice with water, dried overmagnesium sulphate and filtered, and the solvents are evaporated underreduced pressure.

Yield: 20.0 g (90.9% of theory)

¹H-NMR: (200 MHz, CDCl₃): 3.90 (s, 3H), 6.90 (dd, J=10 Hz, J=5 Hz, 1H),7.25 (m, 1H), 7.50 (dd, J=10 Hz, J=4 Hz, 1H), 10.40 (d, J=4 Hz, 1H)

XII.2. (5-Fluoro-2-methoxyphenyl)methanol

20.0 g (0.13 mol) of 5-fluoro-2-methoxybenzaldehyde are dissolved in 205ml of methanol. Under argon, 2.45 g (54.9 mol) of sodium borohydride areadded in small portions. The solution is stirred at RT for 4 hours. Thesolution is concentrated and the residue is taken up in water andstirred for 30 min. The aqueous phase is extracted with ethyl acetateand the organic phase is dried over magnesium sulphate, filtered andevaporated under reduced pressure.

Yield: 19.0 g (93.8% of theory)

¹H-NMR: (300 MHz, CDCl₃): 3.80 (s, 3H), 4.60 (d, J=7 Hz, 2H), 6.80 (dd,J=14 Hz, J=6Hz, 1H), 6.95 (m, 1H), 7.05 (dd, J=6 Hz, J=4Hz, 1H)

XII.3. 2-(Chloromethyl)-4-fluoro-1-methoxybenzene

19.0 g (0.12 mol) of (5-fluoro-2-methoxyphenyl)methanol are dissolved in105 ml of dichloromethane. One drop of DMF is added, and 26.6 ml (0.37mol) of thionyl chloride are then added slowly. The solution is stirredat RT for 2 hours and evaporated under reduced pressure. The residue istaken up in ethyl acetate, the mixture is cooled and admixed with waterand then washed with saturated sodium bicarbonate solution and water,dried over magnesium sulphate and evaporated under reduced pressure.

Yield: 18.0 g (84.5% of theory)

¹H-NMR: (200 MHz, CDCl₃): 3.85 (s, 3H), 4.60 (s, 2H), 6.80 (dd, J=14 Hz,J=6 Hz, 1H), 7.00 (m, 1H), 7.10 (dd, J=6 Hz, J=4 Hz, 1H)

XII.4. (5-Fluoro-2-methoxyphenyl)acetonitrile

18.0 g (0.103 mol) of 2-(chloromethyl)-4-fluoro-1-methoxybenzene aredissolved in DMF:water (5:1) and 30.3 g (0.62 mol) of sodium cyanide anda spatula tip of potassium iodide are added. The solution is stirredovernight at 120° C. The solution is then cooled to RT, water is added,the solution is extracted with ethyl acetate and the extract is driedover magnesium sulphate, filtered and evaporated under reduced pressure.The residue is chromatographed over silica gel using the mobile phasecyclohexane:ethyl acetate (7:3).

Yield: 14.5 g (85.2% of theory)

¹ H-NMR: (200 MHz, CDCl₃): 3.70 (s, 2H), 3.85 (s, 3H), 6.80 (dd, J=14Hz, J=6 Hz, 1H), 7.00 (m, 1H), 7.10 (dd, J=6 Hz, J=4 Hz, 1H)

XII.5. 2-(5-Fluoro-2-methoxyphenyl)ethylamine

Under argon, 17.6 g (132 mmol) of aluminium trichloride are dissolved inTHF, and the mixture is cooled to 0° C. 87 ml of lithium aluminiumhydride solution (1M in THF) are slowly added dropwise. A solution of14.5 g (87.8 mmol) of (5-fluoro-2-methoxyphenyl)acetonitrile in 100 mlis added slowly. The reaction mixture is stirred at RT for 2 hours. At0° C., ice/water is then added, the mixture is made alkaline usingsodium hydroxide solution and extracted with ethyl acetate and theextract is dried and concentrated using a rotary evaporator.

Yield: 10.2 g (68.7% of theory)

¹H-NMR: (200 MHz, CDCl₃): 1.30 (bs, 2H), 2.70 (t, J=6Hz, 2H), 2.90 (t,J=6 Hz, 2H), 3.80 (s, 3H), 6.70-6.90 (m, 3H)

XII.6. Methyl4-({[2-(5-fluoro-2-methoxyphenyl)ethyl]imino}methyl)benzoate

9.00 g (53 mmol) of 2-(5-fluoro-2-methoxyphenyl)ethylamine and 8.73 g(53 mmol) of methyl 4-formylbenzoate are dissolved in 450 ml of ethanol,the mixture is heated at reflux for 2 hours and the solvents are thenevaporated under reduced pressure.

Yield: 17.0 g (100% of theory)

¹H-NMR: (300 MHz, CDCl₃): 3.00 (t, J=6Hz, 2H), 3.80 (s, 3H), 3.85 (t,2H), 3.90 (s, 3H), 6.70-6.90 (m, 3H), 7.75 (d, 2H), 8.10 (d, 2H), 8.20(s, 1H)

XII.7. Methyl4-({[2-(5-fluoro-2-methoxyphenyl)ethyl]amino}methyl)benzoate

5.30 g (16.8 mmol) of methyl4-({[2-(5-fluoro-2-methoxyphenyl)ethyl]imino}-methyl)benzoate aredissolved in 48.4 ml of methanol, and 1.27 g (33.6 mmol) of sodiumborohydride are added. The solution is stirred at RT for 2 hours, andwater is then added and the solution is extracted with ethyl acetate.The organic phase is dried over magnesium sulphate, filtered andconcentrated under reduced pressure. The residue is taken up in ethylacetate and extracted with diluted HCl. The aqueous phase is madealkaline and extracted with ethyl acetate, and the extract is dried overmagnesium sulphate, filtered and concentrated under reduced pressure.

Yield: 4.79 g (89.8% of theory)

¹H-NMR: (200 MHz, CDCl₃): 3.00 (bs, 4H), 3.70 (s, 3H), 3.85 (s, 3H),4.10 (bs, 2H), 6.70 (m, 1H), 6.90 (m, 2H), 7.70 (d, 2H), 8.00 (d, 2H),10.20 (bs, 1H)

XII.8. Methyl4-({(5-ethoxy-5-oxopentyl)[2-(5-fluoro-2-methoxyphenyl)ethyl]-amino}methyl)benzoate

Under argon, 4.70 g (14.8 mmol) of methyl4-({[2-(5-fluoro-2-methoxyphenyl)-ethyl]amino}methyl)benzoate aredissolved in 25 ml of acetonitrile. 3.25 g (15.6 mmol) of ethylbromovalerate, 7.24 g (22.2 mmol) of caesium carbonate and a spatula tipof potassium iodide are added, and the suspension is heated at refluxovernight. The solid is filtered off, the solution is concentrated andthe residue is chromatographed over silica gel (cyclohexane: ethylacetate (4:1)).

Yield: 3.8 g (576% of theory)

¹H-NMR (300 MHz, CDCl₃): 1.20 (t, 3H), 1.50 (m, 4H), 2.30 (t, 2H), 2.50(t, 2H), 2.60-2.80 (m, 4H), 3.65 (s, 2H), 3.70 (s, 3H), 3.90 (s, 3H),4.10 (q, 2H), 6.70 (m, 1H), 6.80 (m, 2H), 7.35 (d, 2H), 7.90 (d, 2H)

XII: Methyl4-({(5-methoxy-5-oxopentyl)[2-(5-fluoro-2-hydroxyphenyl)-ethyl]amino}methyl)benzoate

2.6 g (5.84 mmol) of methyl4-({(5-ethoxy-5-oxopentyl)[2-(5-fluoro-2-methoxy-phenyl)ethyl]amino}methyl)benzoateare dissolved in 50 ml of dichloromethane, the mixture is cooled to 0°C, and 19.3 ml (19.3 mmol) of a 1N solution of boron tribromide indichloromethane are added dropwise. The solution is stirred at 0° C. forone hour. 50 ml of methanol are slowly added dropwise at 0° C., and thereaction mixture is heated at reflux overnight. The mixture is cooledand the solvents are evaporated under reduced pressure. The residue istaken up in ethyl acetate and washed with sodium carbonate, the aqueousphase is extracted three times with ethyl acetate and the combinedorganic phases are washed with saturated sodium chloride solution, driedover magnesium sulphate, filtered and concentrated. The residue ischromatographed over silica gel (cyclohexane:ethyl acetate (5:1) toethyl acetate: methanol (9:1 )).

Yield: 840 mg (34.5% of theory)

¹H-NMR (200 MHz, CDCl₃): 1.60 (m, 4H), 2.20 (m, 2H), 2.50 (m, 2H), 2.80(m, 4H), 3.60 (s, 3H), 3.80 (s, 2H), 3.90 (s, 3H), 6.65 (m, 1H), 6.80(m, 2H), 7.40 (d, 2H), 7.90 (d, 2H), 11.90 (bs, 1H)

XIII: Tert-butyl4-({[2-(2-{[4-(2-phenylethyl)benzyl]oxy}phenyl)ethyl]amino}-methyl)benzoate

This compound was prepared analogously to Ex. I.1 from2-(2-{[4-(2-phenylethyl)-benzyl]oxy}phenyl)ethylamine and tert-butyl4-formylbenzoate.

¹H-NMR (400 MHz, DMSO): 1.50 (s, 9H), 2.60 (m, 4H), 2.80 (m, 4H), 3.80(s, 2H), 5.00 (s, 2H), 6.80 (m, 1H), 6.90 (d, 1H), 7.10-7.40 (m, 13H),7.80 (d, 2H)

XIV: 4′-(Trifluoromethyl)-1,1′-biphenyl-4-carbaldehyde

1 g (4.45 mmol) of 1-bromo-4-(trifluoromethyl)benzene and 0.73 g (4.9mmol) of 4-formylbenzoic acid are added to 30 ml of dimethoxyethane andmixed with 15 ml of 1M sodium carbonate solution. 110 mg oftetrakis(triphenylphosphine)palladium(II) are added, and the mixture isthen heated at reflux temperature for 18 hours. The reaction solution iscooled, dichloromethane and water are added, the mixture is filteredthrough Extrelut and the solvent is distilled off under reducedpressure.

Yield: 87%

¹H-NMR (400 MHz, CDCl₃): 7.70 (m, 6H), 8.00 (d, 2H), 10.00 (s, 1H).

XV: [4′-(Trifluoromethyl)-1,1′-biphenyl-4-yl]methanol

970 mg (3.88 mmol) of the aldehyde XIV are dissolved in methanol and 150mg (3.88 mmol) of sodium hydride are added, the mixture is stirred atroom temperature for 2 hours and concentrated, and water is added. Themixture is stirred for 30 min and the solid is filtered off.

Yield: 90%

¹H-NMR (400 MHz, CDCl₃): 1.75 (t, 1H), 4.80 (d, 2H), 7.40-7.90 (m, 8H).

XVI.: 4-(Chloromethyl)-4′-(trifluoromethyl)-1,1′-biphenyl

883 mg (3.49 mmol) of the alcohol XV are dissolved in dichloromethane,2.5 ml (35 mmol) of POCl₃ are added and the solution is stirred at roomtemperature for 2 hours. The solution is washed with water, dried andconcentrated.

Yield: 85%

XVIIa: [2-(1,1′-Biphenyl-4-ylmethoxy)phenyl]methanol

A mixture of 2.92 g (23.49 mmol) of 2-hydroxybenzyl alcohol, 5.00 g(24.67 mmol) of 4-phenylbenzyl chloride and 3.41 g (24.67 mmol) ofpotassium carbonate in 60 ml of acetone was heated at reflux overnight.The precipitate formed was filtered off. The residue was taken up in 1NNaOH, and the mixture was extracted with ethyl acetate. The combinedorganic phases were dried over Na₂SO₄ and the solvent was removed. Theproduct was purified chromatographically (silica gel, cyclohexane/ethylacetate 10:1).

Yield: 4.27 g (62.7%)

¹H NMR (300 MHz, CDCl₃): δ=2.26 (t, J=5.7 Hz, 1H), 4.75 (d, J=5.7 Hz,2H), 5.16 (s, 2H), 6.88 -7.02 (m, 2H), 7.18 -7.66 (m, 11H).

The following compounds were prepared analogously: Physical data: ¹H-NMR(δ in ppm, Yield selection) or LC/MS Example Structure (%)(mass/retention time [min]) XVIIb (from 5- bromo-pentyl- benzene)

86.4 ¹H NMR (300 MHz, CDCl₃): δ = 1.43-1.58 (m, 2H), 1.62-1.77 (m, 2H),1.77-1.93 (m, 2H), 2.28 (bs, 1H), 2.64 (t, J=7.7 Hz, 2H), 4.00 (t, J=6.4Hz, 2H), 4.66 (s, 2H), 6.80-6.97 (m, 2H), 7.10-7.34 (m, 7H). XVIIc (from5- cyclo-hexyl- benzyl- chloride)

90.1 ¹H NMR (300 MHz, CDCl₃): δ = 1.14-2.59 (m, 12H), 4.71 (s, 2H), 5.07(s, 2H), 6.80-7.39 (m, 8H). XVIId (from 4- phenyl-ethyl- benzylchloride)

56.1 ¹H NMR (400 MHz, CDCl₃): δ = 2.30 (t, J=6.1 Hz, 1H), 2.93 (s, 4H),4.72 (d, J=6.1 Hz, 2H), 5.08 (s, 2H), 6.91-6.99 (m, 2H), 7.14-7.35 (m,11H).

XVIIIa: [2-(1,1′-Biphenyl-4-ylmethoxy)phenyl]acetonitrile

A solution of 15.20 g (52.35 mmol) of XVIIa in 300 ml of benzene wasadded dropwise to a solution of 6.49 ml (88.99 mmol) of thionyl chloridein 150 ml of benzene. The solution was heated at reflux for 2 h. Thesolvent was removed and the residue was taken up in 350 ml of DMF. 25.65g (523.48 mmol) of NaCN were added, and the mixture was heated at refluxfor 16 h. After the mixture had cooled to room temperature, it wasadmixed with water and the precipitate was filtered off with suction.

Yield: 13.6 g (81.5%)

¹H-NMR (400 MHz, CDCl₃): δ=3.74 (s, 2H), 5.16 (s, 2H), 6.93 -7.03 (m,2H), 7.21 -7.67 (m, 11H).

The following compounds were prepared analogously: Physical data: ¹H-NMR(δ in ppm, Yield selection) or LC/MS Example Structure (%)(mass/retention time [min]) XVIIIb (from XVIIc)

47.1 ¹H NMR (400 MHz, CDCl₃): δ = 1.17-1.95 (m, 10H), 2.43-2.60 (m, 1H),3.72 (s, 2H), 5.07 (s, 2H), 6.89-7.02 (m, 2H), 7.18-7.41 (m, 6H). XVIIIc(from XVIId)

75.0 ¹H NMR (400 MHz, CDCl₃): δ = 2.93 (s, 4H), 3.71 (s, 2H), 5.08 (s,2H), 6.89-7.03 (m, 2H), 7.12-7.43 (m, 11H).

XIXa: 2-[2-(1,1′-Biphenyl-4-ylmethoxy)phenyl]ethanamine hydrochloride

A solution of 7.90 g (26.39 mmol) of XVIIIa in 80 ml of THF was addeddropwise to a solution of 52.93 ml (52.93 mmol) of BH₃.THF (1 M in THF).The solution was heated at reflux for 2 h. After the solution had cooledto room temperature, it was mixed very carefully with 150 ml of 6 Mhydrochloric acid, and the mixture was stirred at room temperature for16 h. The precipitate that had formed was filtered off and dried underhigh vacuum.

Yield: 6.72 g (74.9%)

¹H NMR (400 MHz, DMSO-d₆): δ=2.89-3.01 (m, 4H), 5.20 (s, 2H), 6.85-7.78(m, 13H), 7.99 (bs, 3H).

The following compounds were prepared analogously: Physical data: ¹H-NMR(δ in ppm, Yield selection) or LC/MS Example Structure (%)(mass/retention time [min]) XIXb (from XVIIIb)

70.3 ¹H NMR (400 MHz, DMSO-d₆): δ = 1.09-1.46 (m, 6H), 1.57-1.85 (m,5H), 2.75-2.95 (m, 2H), 2.96-3.05 (m, 2H), 5.09 (s, 2H), 6.77-7.44 (m,8H), 7.77 (bs, 3H). XIXc (from XVIIIc)

83.1 ¹H NMR (300 MHz, DMSO-d₆): δ = 2.69-3.06 (m, 8H), 5.10 (s, 2H),6.83-7.42 (m, 13H), 7.95 (bs, 3H).

XXa: tert-Butyl5-({2-[2-(1,1′-biphenyl-4-ylmethoxy)phenyl]-ethyl}amino)pentanoate

13.40 g (132.40 mmol) of triethylamine and 1.05 g (4.41 mmol) oftert-butyl bromovalerate were added to a solution of 3.00 g (8.83 mmol)of XVIIIa in 50 ml of DMF. The mixture was stirred at room temperaturefor 16 h, and the reaction was monitored by thin-layer chromatography.The solution was admixed with water and extracted with ethylacetate/cyclohexane 1:1. The combined organic phases were dried overNa₂SO₄ and the solvent was removed. The product was purifiedchromatographically (silica gel, CH₂Cl₂/MeOH 20:1).

Yield: 0.85 g (41.9%).

¹H-NMR (300 MHz, DMSO-d₆): δ=1.31-1.54 (m, 4H), 1.36 (s, 9H), 2.15 (t,J=7.2 Hz, 2H), 2.56 (t, J=6.8 Hz, 2H), 2.70-2.91 (m, 5H), 5.17 (s, 2H),6.82-7.75 (m, 13H).

The following compounds were prepared analogously: Physical data: ¹H-NMR(δ in ppm, Yield selection) or LC/MS Example Structure (%)(mass/retention time [min]) XXb (from XIXb)

68.5 ¹H NMR (400 MHz, CDCl₃): δ = 1.16-1.95 (m, 21H), 2.19 (t, J 0 7.3Hz, 2H), 2.43-2.66 (m, 4H), 2.76-3.00 (m, 6H), 5.03 (s, 2H), 6.82-7.42(m, 8H). XXc (from XIXc)

90.4 LC/MS: 4.04 min [488 (M + H)].

XXI: Methyl4-{[{2-[2-({4-[2-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-ethyl]benzyl}oxy)phenyl]ethyl}(5-ethoxy-5-oxopentyl)amino]methyl}benzoate

166 mg (0.403 mmol) of methyl4-({(5-ethoxy-5-oxopentyl)-[2-(2-hydroxyphenyl)ethyl]amino}methyl)benzoateand 160 mg (0.443 mmol) oftert-butyl(4-{2-[4-(chloromethyl)phenyl]ethyl}phenoxy)dimethylsilane(prepared from 4-{[tert-butyl(dimethyl)silyl]oxy}benzaldehyde and[4-(methoxycarbonyl)-benzyl](triphenyl)phosphonium chloride via a Wittigreaction, subsequent hydrogenation of the double bond, reduction withlithium aluminium hydride and chlorination analogously to XVI) aredissolved in 6 ml of acetonitrile. 263 mg (0.81 mmol) of caesiumcarbonate and a spatula tip of potassium iodide are added, and themixture is heated at reflux overnight. The suspension is filtered andconcentrated and the residue is chromatographed over silica gel(cyclohexane: ethyl acetate=5: 1).

Yield: 27 mg (9.1% of theory)

LC/MS: 738 (M+1), Rt=3.76

Conditions: column: Symmetry C18 2.1*150 mm; mobile phase:acetonitrile+0.6 g of 30% strength HCl/11 of H₂O; gradient: 10%acetonitrile to 90% acetonitrile; flow rate: 0.6 ml/min; detector: UV210 nm

Synthesis Examples Example 1 Methyl4-{[{2-[(2-chlorobenzyl)oxy]phenethyl}(5-methoxy-5-oxopentyl)-amino]methyl}benzoate(by Process D)

193.2 mg (0.484 mmol) of methyl4-{[(2-hydroxyphenethyl)amino]methyl}benzoate from Ex. I, 77.9 mg (0.484mmol) of 2-chlorobenzyl chloride and 80.2 mg (0.580 mmol) of potassiumcarbonate in 2.0 ml of acetonitrile are heated at reflux for 18 hours.The batch is poured into water and extracted with ethyl acetate. Afterdrying over magnesium sulphate and distillative removal of the solventunder reduced pressure the crude product is purified by flashchromatography over silica gel (0.04-0.063 nm) using cyclohexane/ethylacetate 2/1 as mobile phase.

Yield: 245.2 mg (83.5% of theory)

¹H-NMR (200 MHz, d⁶-DMSO): δ=1.40 (m, 4H), 2.15 (t, 2H), 2.40 (dd, 2H),2.57 (m, 2H), 2.72 (m, 2H), 3.53 (s, 3H), 3.82 (s, 3H), 5.08 (s, 2H),6.9-7.5 (m, 10H), 7.82 (d, 2H).

Example 24-[((4-carboxybutyl){2-[(2-chlorobenzyl)oxy]phenethyl}amino)methyl]-benzoicacid (by Process E)

124.8 mg (0.238 mmol) of methyl4-{[{2-[(2-chlorobenzyl)-oxy]phenethyl}(5-methoxy-5-oxopentyl)amino]methyl}benzoatefrom Ex. 1 are initially charged in 0.3 ml of methanol and 0.17 ml ofwater and admixed with 0.2 ml of a 40% strength sodium hydroxidesolution. The mixture is stirred at 60° C. for one hour and then cooled,and the methanol is distilled off under reduced pressure. The aqueousphase is adjusted to pH 4 by addition of a citric acid/aqueous sodiumhydroxide solution buffer and the resulting precipitate is separatedoff. Tituration with boiling cyclohexane gives a finely crystallineproduct.

Yield: 65.70 mg (54.4% of theory)

¹H NMR (200 MHz, d⁶-DMSO): δ=1.35 (br.m 4H), 1.98 (br. m, 2H), 2.37 (m(2H), 2.58 (m, 2H), 2.70 (m, 2H), 5.12 (s, 2H), 6.8-7.6 (m, 10H), 7.75(d, 2H), 13.5 (br.s, 1H).

Example 3 Methyl4-[((5-ethoxy-3,3-dimethyl-2,5-dioxopentyl){2-[(5-phenylpentyl)oxy]phenethyl}amino)methyl]benzoate(by Process A)

200.0 mg (0.463 mmol) of methyl4-[({2-[(5-phenylpentyl)oxy]phenethyl}amino)-methyl]benzoate from Ex. V,116.4 mg (0.463 mmol) of ethyl 5-bromo-3,3-dimethyllaevulinate and 58.9mg (0.56 mmol) of sodium carbonate in 1 ml of acetonitrile are heated at60° C. for 18 hours. The solvent is distilled off using a rotaryevaporator and the residue is poured into water and extracted with ethylacetate. The organic phase is washed with saturated sodium chloridesolution, dried over magnesium sulphate and concentrated. The crudeproduct is purified by chromatography over silica gel (0.04-0.063 nm)using cyclohexane/ethyl acetate 10/1.

Yield: 163.1 mg (58.5% of theory)

¹H-NMR (200 MHz, d⁶-DMSO): δ=1.09 (s, 6H), 1.10 (t, 3H), 1.35 (m, 2H),1.60 (m, 4H), 2.55 (m, 2H), 2.70 (s, 2H), 3.75 (s, 3H), 3.96 (q, 2H),6.7-6.9 (m, 2H), 7.0-7.3 (m, 7H), 7.40 (d, 2H), 7.85 (d, 2H).

Example 4 Methyl4-{[{2-[(4-bromobenzyl)oxy]phenethyl}(5-ethoxy-5-oxopentyl)amino]methyl}benzoate(by Process D)

5.00 g (11.0 mmol) of methyl4-[({2-[(4-bromobenzyl)oxy]phenethyl}amino)-methyl]benzoate from Ex.VIII, 2.30 g (11.0 mmol) of ethyl 5-bromovalerate and 1.109 g (13.21mmol) of sodium bicarbonate in 30 ml of acetonitrile are heated atreflux for 18 hours. The reaction mixture is admixed with water andextracted with methylene chloride. The organic phase is washed withsaturated sodium chloride solution and dried over magnesium sulphate andthe solvent is distilled off under reduced pressure. The residue ispurified by chromatography over silica gel using the mobile phasemethylene chloride/methanol 100/1.

Yield: 5.69 g (88.1% of theory)

¹H-NMR (200 MHz, d⁶-DMSO): δ=1.1 (m, 2H), 1.4 (m, 2H), 2.15 (t, 3H), 2.4(t, 2H), 2.6 (m, 2H), 2.8 (m, 2H), 3.63 (s, 2H), 3.80 (s, 2H), 4.0(q,2H), 5.10 (s, 2H), 6.85 (t, 2H), 7.0-7.2 (m, 8H), 7.4-7.8 (m), 7.9 (d,2H)

Example 5 Methyl4-{[{2-[(4′-chloro[1,1′-biphenyl]-4-yl)methoxy]phenethyl}(5-ethoxy-5-oxopentyl)amino]methyl}benzoate(by Process F)

300.0 mg (0.51 mmol) of methyl4-{[{2-[(4-bromobenzyl)oxy]phenethyl}(5-ethoxy-5-oxopentyl)amino]methyl}benzoatefrom Ex. 4 are initially charged in 3 ml of dimethoxyethane and admixedsuccessively with 101.7 mg (0.62 mmol) of 4-chlorophenylboronic acid and0.57 ml of 2M sodium carbonate solution. 10.0 mg ofdichlorobis(triphenylphosphine)palladium(II) are added, and the mixtureis then heated at reflux temperature for 18 hours. The reaction solutionis cooled, admixed with 20 ml of ethyl acetate and washed successivelywith 5% strength sodium hydrogen phosphate solution, water and saturatedsodium chloride solution. The organic phase is dried over magnesiumsulphate and the solvent is distilled off under reduced pressure. Thecrude product is chromatographed over silica gel using the mobile phasecyclohexane/ethyl acetate=10:1.

Yield: 240.5 mg (74.3% of theory)

¹H-NMR (200 MHz, d⁶-DMSO): δ=1.10 (t, 3H), 1.43 (m, 4H), 2.15 (t, 2H),2.45 (t, 2H), 2.62 (m, 2H), 2.75 (m, 2H), 3.63 (s, 2H), 3.80 (s, 3H),3.97 (q, 2H), 5.09 (s, 2H), 6.85 (t, 1H), 7.01 (d, 1H), 7.13 (dd, 2H),7.36 (d, 2H), 7.5-7.7 (m, 8H), 7.83 (d, 2H).

Example 6 Methyl4-([(5-methoxy-5-oxopentyl)[2-({4-[(E)-2-phenylethenyl]benzyl}-oxy)phenethyl]amino}methyl)benzoate(by Process D)

1.0 g (2.50 mmol) of methyl4-{[(2-hydroxyphenethyl)-(5-methoxy-5-oxopentyl)-amino]methyl}benzoatefrom Ex. I, 0.687 g (3.00 mmol) of 4-(chloromethyl)stilbene and 0.520 g(3.75 mmol) of potassium carbonate in 10.0 ml of acetonitrile are heatedat reflux for 18 hours. The solution is filtered and the solvent isdistilled off under reduced pressure. The crude product is purified bychromatography over silica gel using the mobile phase cyclohexane/ethylacetate 4/1.

Yield: 1.32 g (79.9% of theory)

¹H-NMR (300 MHz, d⁶-DMSO): δ=1.4-1.6 (m, 4H), 2.17 (t, 2H), 2.43 (t,2H), 2.6 (m, 2H), 2.75 (m, 2H, 3.55 (s, 3H), 3.64 (s, 2H), 3.70 (s, 3H),5.05 (s, 2H), 6.7-7.4 (m, 11H), 7.55 (t, 4H), 7.85 (d, 2H).

Example 7 Methyl4-[((5-methoxy-5-oxopentyl)[2-[(4-phenethylbenzyl)oxy]-phenethyl}amino)methyl]benzoate(by Process G)

781.8 mg (1.34 mmol) of methyl4-({(5-methoxy-5-oxopentyl)[2-({4-[(E)-2-phenyl-ethenyl]benzyl}oxy)phenethyl]amino}methyl)benzoatefrom Ex. 6 and 80.0 mg of 10% palladium on activated carbon in 10 ml ofethyl acetate are hydrogenated under atmospheric pressure. After I hour,the calculated amount of hydrogen has been taken up. The solution isfiltered and the solvent distilled off under reduced pressure. The crudeproduct is purified by chromatography over silica gel using the mobilephase cyclohexane/ethyl acetate=10:1.

Yield: 309 mg (38.9% of theory)

¹H-NMR (300 MHz, d⁶-DMSO): δ=1.42 (m, 4H), 2.15 (t, 2H), 2.41 (t, 2H),2.57 (m, 2H), 2.72 (m, 2H), 2.85 (s, 4H), 3.55 (s, 3H), 3.60 (s, 2H),3.82 (s, 2H), 4.98 (s, 2H), 6.8-7.4 (m, 15H), 7.85 (d, 2H).

Example 84-[((4-Carboxybutyl)-{2-[(4-phenethylbenzyl)oxy]phenethyl}amino)-methyl]benzoicacid hydrochloride (by process E)

262.60 mg (0.442 mmol) of methyl4-[((5-methoxy-5-oxopentyl){2-[(4-phenethyl-benzyl)oxy]phenethyl}amino)methyl]benzoatefrom Ex. 7 are initially charged in 2 ml of dioxane and admixed with 0.2ml of 45 per cent strength NaOH, and the mixture is heated at 60° C. for18 hours. The dioxane is distilled off under reduced pressure and theresidue is taken up in water and adjusted to pH 4 using 2N HCl. Theresulting precipitate is filtered off and dried. 50 mg of the productare dissolved in 2 ml of methylene chloride and 1 ml of methanol, andthe mixture is admixed with 1 ml of a 4N solution of HCl in dioxane andstirred at room temperature for 1 h. The solvent is distilled off underreduced pressure and the residue is stirred with ether/petroleum ether.

Yield: 34.0 mg (56.2% of theory) white crystals

¹H-NMR (300 MHz, d⁴-methanol): δ=1.52 (m, 2H), 1.72 (m, 2H), 2.25 (t,2H), 2.90 (m, 4H), 3.15 (m, 2H), 3.30 (m, 4H), 4.38 (s, 2H), 5.08 (s,2H), 6.8-7.3 (m, 13H), 7.55 (d, 2H), 8.05 (d, 2H).

Example 8a4-[((4-Carboxybutyl)-{2-[(4-phenethylbenzyl)oxy]phenethyl}amino)-methyl]benzoicacid

The free carboxylic acid was prepared by the same route, but without thelast step, i.e. the reaction with HCl:

¹H-NMR (300 MHz, d⁶-DMSO): δ=1.45 (m, 4H), 2.10 (m, 2H), 2.30-3.60 (m),5.08 (s, 2H), 6.80 (m, 1H), 6.90 (m, 1H), 7.00-7.50 (m, 13H), 12.5 (bs).

The following compounds can be prepared analogously: Physical data:¹H-NMR (δ in ppm, selection)¹⁾ or LC/MS Example Structure(mass/retention time [min])²⁾ 9 (from I and 5-phenylpentyl 1-bromide byprocess D)

2.40(dd), 2.57(m), 2.72(m), 3.53(s), 3.60(s), 3.82(s), 3.82(s) 10 (fromI and 4-phenylbutyl 1- bromide by process D)

2.41(dd), 2.59(m), 2.73(m), 3.54(s), 3.63(s), 3.84(s), 3.83(s) 11 (from9 by process E)

2.45(dd), 2.55(m), 2.68(m), 3.62(s), 3.85(t), 12.3(br.s) 12 (from 10 byprocess E)

2.43(dd), 2.57(m), 2.66(m), 3.64(s), 3.87(t), 12.3(br.s) 13 (from IIIand 4- (chloro-methyl) stilbene by process D)

592 (M + 1), Rt = 4.23 14 (from I and allyl bromide by process D)

2.40(dd), 2.57(m), 2.72(m), 3.53(s), 3.60(s), 3.82(s), 3.89(d) 15 (from14 by process E)

2.44(dd), 2.56(m), 2.65(m), 3.65(s), 3.87(d), 12.3(br.s) 16 (from I and4- (chloro-methyl) biphenyl by process D)

2.40(dd), 2.57(m), 2.72(m), 3.53(s), 3.60(s), 3.82(s), 5.08(s) 17 (fromI and 4- (4′-chloro)- phenoxybenzyl chloride by process D)

2.42(dd), 2.59(m), 2.73(m), 3.54(s), 3.62(s), 3.84(s), 5.10(s) 18 (fromI and 4-ethylbenzyl chloride by process D)

2.41 (dd), 2.55(m), 2.70(m), 3.55(s), 3.62(s), 3.84(s), 5.08(s) 19 (fromI and 4-t-butylbenzyl chloride by process D)

2.39(dd), 2.59(m), 2.70(m), 3.55(s), 3.62(s), 3.84(s), 5.10(s) 20 (fromI and 4-chlorobenzyl chloride by process D)

2.40(dd), 2.55(m), 2.74(m), 3.52(s), 3.55(s), 3.75(s), 5.05(s) 21 (fromI and 4-phenylmethyl- oxybenzyl chloride by process D)

2.44(dd), 2.58(m), 2.69(m), 3.55(s), 3.64(s), 3.83(s), 5.06(s) 22 (fromI and 4-methoxy- benzyl chloride by process D)

2.39(dd), 2.59(m), 2.70(m), 3.55(s), 3.62(s), 3.84(s), 5.10(s) 23 (fromI and 3-trifluoro- methylbenzyl chloride by process D)

2.42(dd), 2.59(m), 2.73(m), 3.54(s), 3.62(s), 3.84(s), 5.10(s) 24 (fromI and 4-allylbenzyl chloride by process D)

2.41(dd), 2.55(m), 2.70(m), 3.55(s), 3.62(s), 3.84(s), 5.08(s) 25 (fromI and 3-bromo-1- propine by process D)

2.40(dd), 2.57(m), 2.72(m), 3.53(s), 3.60(s), 3.82(s), 3.91(d) 26 (fromI and 4-methylbenzyl chloride by process D)

2.40(dd), 2.57(m), 2.72(m), 3.53(s), 3.60(s), 3.82(s), 5.08(s) 27 (from16 by process E)

2.37(dd), 2.58(m), 2.72(m), 3.61(s), 5.12(s), 12.3(br.s) 28 (from 17 byprocess E)

2.43(dd), 2.61(m), 2.75(m), 3.61(s), 5.03(s), 12.3(br.s) 29 (from 18 byprocess E)

2.40(dd), 2.62(m), 2.72(m), 3.63(s), 5.05(s), 12.3(br.s) 30 (from 19 byprocess E)

2.37(dd), 2.58(m), 2.72(m), 3.61(s), 5.12(s), 12.3(br.s) 31 (from 20 byprocess E)

2.43(dd), 2.61(m), 2.75(m), 3.61(s), 5.03(s), 12.3(br.s) 32 (from 21 byprocess E)

2.43(dd), 2.61(m), 2.75(m), 3.61(s), 5.03(s), 12.3(br.s) 33 (from 6 byprocess E)

2.37(dd), 2.58(m), 2.72(m), 3.61(s), 5.12(s), 12.3(br.s) 34 (from 22 byprocess E)

2.43(dd), 2.61(m), 2.75(m), 3.61(s), 5.03(s), 12.3(br.s) 35 (from 23 byprocess E)

2.37(dd), 2.58(m), 2.72(m), 3.61(s), 5.12(s) 36 (from 24 by process E)

2.43(dd), 2.61(m), 2.75(m), 3.61(s), 5.03(s), 12.3(br.s) 37 (from 25 byprocess E)

2.44(dd), 2.56(m), 2.65(m), 3.65(s), 3.90(d), 12.3(br.s) 38 (from 26 byprocess E)

2.37(dd), 2.58(m), 2.72(m), 3.61(s), 5.12(s), 12.3(br.s) 39 (from V andethyl 6-bromohexanoate by process A) 1.00-1.20 (m), 1.30-1.60 (m), 2.20(t), 2.30-2.70 (m), 3.60 (s), 3.80 (m), 4.00 (q), 6.80 (m), 7.00-7.30(m), 7.40 (d), 7.90 (d) 40 (from 39 by process E)

1.22 (m), 1.40 (m), 1.60 (m), 2.15 (t), 2.40-2.60 (m), 2.70 (m), 3.65(s), 3.86 (t), 6.75-6.9 (m), 7.0-7.3 (m), 7.35 (d), 7.90(d), 12.30 (bs).41 (from V and ethyl 4-bromobutanoate by process A)

546 (M + 1), Rt = 4.01 42 (from V and ethyl 4-bromo-2- butenoate byprocess A)

544 (M + 1), Rt = 4.12 43 (from V and ethyl 3-bromo- propanoate byprocess A)

518 (M + 1), Rt = 4.27 44 (from V and diethyl 2-(3-bromo-propyl)malonate by process A)

518 (M + 1), Rt = 4.25 45 (from V and N- ethoxycarbonylmethyl)-2-chloro- acetamide by process A)

575 (M + 1), Rt = 4.34 46 (from 45 by process E)

1.35 (m), 1.60 (m), 2.45 (s), 2.60 (m), 2.75 (m), 3.15 (s), 3.75 (s),3.85 (t), 6.7-6.9 (m), 7.0-7.1 (m), 7.3 (d), 7.45 (d), 7.85 (d) 47 (fromVI and ethyl 5-bromo- pentanoate by process A)

1.0-1.6 (m), 2.2 (t), 2.4 (m), 2.55 (m), 2.60 (m), 3.65 (s), 3.85 (s),4.05 (q), 6.8-6.9 (m), 7.0-7.2 (m), 7.4 (d), 7.9 (d) 48 (from VI andethyl 6-bromohexanoate by process A)

1.0-1.6 (m), 2.2 (t), 2.4 (m), 2.55 (m), 2.60 (m), 3.65 (s), 3.85 (s),4.05 (q), 6.8-6.9 (m), 7.0-7.2 (m), 7.4 (d), 7.9 (d) 49 (from VII andethyl 6-bromohexanoate by process A)

1.1 (m), 1.4 (m), 2.15 (t), 2.4 (t), 2.6 (m), 2.8 (m), 3.63 (s), 3.80(s), 4.0 (q), 5.10 (s), 6.85 (t), 7.0-7.2 (m), 7.4-7.8 (m), 7.9 (d) 50(from 41 by process E)

504 (M + 1), Rt = 3.30 51 (from 42 by process E)

502 (M + 1), Rt = 3.34 52 (from 44 by process E)

562 (M + 1), Rt = 3.31 53 (from 43 by process E)

490 (M + 1), Rt = 3.34 54 (from 47 by process E)

1.0-1.6 (m), 2.2 (t), 2.4 (m), 2.55 (m), 2.60 (m), 3.65 (s), 3.85 (s),4.05 (q), 6.8-6.9 (m), 7.0-7.2 (m), 7.4 (d), 7.9 (d), 12.5 (br. S) 55(from 48 by process E)

1.0-1.6 (m), 2.2 (t), 2.4 (m), 2.55 (m), 2.60 (m), 3.65 (s), 3.85 (s),4.05 (q), 6.8-6.9 (m), 7.0-7.2 (m), 7.4 (d), 7.9 (d), 12.5 (br. S) 56(from 49 by process E)

1.2 (m), 1.4 (m), 1.7 (m), 2.1 (t), 3.0-3.3 (m), 4.4 (s), 5.15 (s),7.0-7.8 (m), 8.0 (d), 12.5 (br. s) 57 (from 4 by process E)

1.4 (m), 2.1 (m), 2.3-2.7 (m), 3.65 (m), 5.05 (s), 7.0-7.8 (m), 12.4(br. s) 58 (from I and 4- cyclohexyl- benzyl chloride by process D)

572 (M + 1), Rt = 3.43 59 (from I and 4-(4,5,6- trichloro-pyrimidin-2-yl)benzyl chloride by process D)

670 (M + 1), Rt = 3.39 60 (from I and 4-(2- trifluoro- methylthiazol-4-yl)benzyl chloride by process D)

641 (M + 1), Rt = 3.79 61 (from I and 5-(4- methoxy-phenyl)- 3-chloro-methyl1,2,4-oxa- diazole by process D)

588 (M + 1), Rt = 3.45 62 (from I and 2- phenyl-4- chloromethyl-thiazole by process D)

573 (M + 1), Rt = 3.51 63 (from I and 4-1,2,3- thiadiazol-4-yl-benzylchloride by process D)

574 (M + 1), Rt = 3.40 64 (from I and 4- trifluoromethyl-mercaptyl-benzyl chloride by process D)

590 (M + 1), Rt = 3.74 65 (from I and 4- fluoro-3- phenoxybenzylchloride by process D)

600 (M + 1), Rt = 3.72 66 (from I and 2- chloromethyl- 5,6,7,8-tetra-hydronaphthalene by process D)

544 (M + 1), Rt = 3.74 67 (from II and (4-chloro- methyl)stilbene byprocess D)

592 (M + 1), Rt = 3.70 68 (from I and 4- nitrobenzyl chloride by processD)

1.1 (m), 1.4(m), 2.15 (t), 2.4 (t), 2.6 (m), 2.8 (m), 3.63 (s), 3.80(s), 4.0 (q), 5.10 (s), 6.85 (t), 7.0-7.2 (m), 7.4-7.8 (m), 7.9 (d) 69(from 4 and 4- methylphenyl- boronic acid by process F)

594 (M + 1), Rt = 3.39 70 (from 58 by process E)

544 (M + 1), Rt = 3.62 71 (from 59 by process E)

643 (M + 1), Rt = 3.30 72 (from 60 by process E)

612 (M + 1), Rt = 3.47 73 (from 62 by process E)

545 (M + 1), Rt = 3.18 74 (from 64 by process E)

562 (M + 1), Rt = 3.39 75 (from 65 by process E)

572 (M + 1), Rt = 3.40 76 (from 66 by process E)

516 (M + 1), Rt = 3.38 77 (from 4 and 4-methoxyphenyl- boronic acid byprocess F)

610 (M + 1), Rt = 3.41 78 (from I and 4- phenylamino- carbonylbenzylchloride by process D)

609 (M + 1), Rt = 3.39 79 (from I and 2-(4- chloro- phenyl)-4-chloro-methylthiazole by process D)

608 (M + 1), Rt = 3.43 80 (from I and 4- phenoxybutyl- oxybenzylchloride by process D)

654 (M + 1), Rt = 3.45 81 (from I and 3- phenoxybenzyl chloride byprocess D)

582 (M + 1), Rt = 3.34 82 (from I and 4-(4,6- dichloro- pyrimidin-2-yl)-mercaptobenzyl chloride by process D)

628 (M + 1), Rt = 3.19 83 (from I and 4-(4- cyanophenoxy)- benzylchloride by process D)

607 (M + 1), Rt = 3.22 84 (from I and 4-(4- trifluoromethyl-phenoxybenzyl chloride by process D)

650 (M + 1), Rt = 4.01 85 (from I and 4-(4- tolyl- sulphonyl-methylbenzyl bromide by process D)

658 (M + 1), Rt = 3.85 86 (from 84 by process E)

622 (M + 1), Rt = 3.62 87 (from 5 by process E)

1.2(m), 1.4(m), 1.7 (m), 2.1 (t), 3.0-3.3 (m), 4.4 (s), 5.15 (s),7.0-7.8 (m), 8.0 (d), 12.5 (br. s) 88 (from 77 by process E)

1.2(m), 1.4(m), 1.7 (m), 2.1 (t), 3.0-3.3 (m), 3.9 (s), 4.4 (s), 5.15(s), 7.0-7.8 (m), 8.0 (d), 12.5 (br. s) 89 (from 4 and 3- thiophene-boronic acid by process F)

586 (M + 1), Rt = 4.21 90 (from 4 and 3- chlorophenyl- boronic acid byprocess F)

615 (M + 1), Rt = 4.19 91 (from 4 and 3- methylcarbonyl- aminophenyl-boronic acid by process F)

637 (M + 1), Rt = 4.30 92 (from 4 and 2- methoxyphenyl- boronic acid byprocess F)

610 (M + 1), Rt = 4.25 93 (from 4 and 3- nitrophenyl- boronic acid byprocess F)

625 (M + 1), Rt = 4.19 94 (from 4 and 2,4- dichlorophenyl- boronic acidby process F)

649 (M + 1), Rt = 4.25 95 (from 4 and 3- methylphenyl- boronic acid byprocess F)

594 (M + 1), Rt = 4.33 96 (from 4 and 3- chloro-4-fluoro- phenylboronicacid by process F)

633 (M + 1), Rt = 4.23 97 (from 4 and 3- aminophenyl- boronic acid byprocess F)

595 (M + 1), Rt = 3.23 98 (from V and methyl 4-(2-bromo-ethyloxy)benzoate by process A and E)

882 (M + 1), Rt = 3.45 99 (from 67 by process E)

550 (M + 1), Rt = 3.38 100 (from IX and 4- cyclohexyl- benzyl chlorideby process D)

1.30 (t, 3H), 1.50-2.00 (m, 10H), 2.50 (m, 1H), 2.90 (m, 6H), 3.80 (s,2H), 3.95 (m, 5H), 4.40 (q, 2H), 5.00 (s, 2H), 6.70-6.90 (m, 4H),7.10-7.40 (m,8H), 8.00 (m, 4H). 101 (from IX and octyl chloride byprocess D)

0.90 (m, 3H), 1.20-1.80 (m, 15H), 2.80 (s, 4H), 3.00 (t, 3H), 3.80-3.90(m, 7H), 4.05 (t, 2H), 4.40 (q, 2H), 6.70-6.90 (m, 4H), 7.10-7.40 (m,8H), 8.00 (m, 4H). 102 (from 100 by process E)

1.40-1.20 (m, 5H), 1.60-1.90 (m, 5H), 2.40 (m, 1H), 3.20 (m, 2H), 3.40(m, 2H), 3.60 (m, 2H), 4.25 (m, 2H), 4.50 (m, 2H), 5.00 (s, 2H), 6.90(m, 3H), 7.10 (m, 3H), 7.30 (m, 4H), 7.50 (d, 2H), 7.90 (d, 2H), 8.00(d, 2H). 103 (from 101 by process E)

0.90 (t, 3H), 1.40-1.20 (m, 10H), 1.60 (m, 2H), 3.00 (m, 2H), 3.20 (m,2H), 3.40 (m, 2H), 3.90 (t, 2H), 4.30 (m, 4H), 6.90 (m, 2H), 7.00 (m,2H), 7.20 (m, 2H), 7.50 (d, 2H), 7.95 (d, 2H), 8.05 (d, 2H). 104 (from94 by process E)

2.37(dd), 2.58(m), 2.72(m), 3.61(s), 5.12(s), 12.3(br.s) 105 (from 4 and4- fluorophenyl- boronic acid by process F)

1.1 (m), 1.4 (m), 2.15 (t), 2.4 (t), 2.6 (m), 2.8 (m), 3.63 (s), 3.80(s), 4.0 (q), 5.10 (s), 6.85 (t), 7.0-7.2 (m), 7.4-7.8 (m), 7.9 (d) 106(from 105 by process E)

555 (M + 1), Rt = 3.32 107 (from I and 1,5-dibromo- pentane by processD)

561 (M + 1), Rt = 3.53 108 (from I and 1,2- dibromo- ethane by processD)

519 (M + 1), Rt = 3.65 109 (from IX and 4-ethylbenzyl chloride byprocess D)

1.30 (t, 3H), 1.40 (t, 3H), 2.50 (q, 2H), 2.90 (m, 6H), 3.80 (s, 2H),3.95 (m, 5H), 4.30 (q, 2H), 4.90 (s, 2H), 6.70-6.90 (m, 4H), 7.10-7.40(m, 8H), 8.00 (m, 4H). 110 (from IX and 4- butylbenzyl chloride byprocess D)

1.30 (t, 3H), 1.40 (t, 3H), 1.50 (m, 4H), 2.50 (m, 2H), 2.90 (m, 6H),3.80 (s, 2H), 3.95 (m, 5H), 4.30 (q, 2H), 4.90 (s, 2H), 6.70-6.90 (m,4H), 7.10-7.40 (m, 8H), 8.00 (m, 4H). 111 (from I and 2- [4-(chloro-methyl)phenyl]- 5-methyl-1,3- benzoxazole by process D)

1.60 (m, 4H), 2.20 (t, 2H), 2.70 (m, 9H), 3.60 (m, 5H), 3.90 (s, 3H),5.00 (s, 2H), 6.80-7.60 (m, 11H), 7.90 (d, 2H), 8.10 (d, 2H) 112 (from Iand 4- phenylthio- benzyl chloride by process D)

1.60 (m, 4H), 2.20 (t, 2H), 2.70 (m, 6H), 3.60 (m, 5H), 3.90 (s, 3H),5.00 (s, 2H), 6.80-7.60 (m, 15H), 7.90 (d, 2H) 113 (from X and 4-(chloromethyl)-4′- propyl-1,1′- biphenyl by process D)

1.00 (t, 3H), 1.70 (m, 6H), 2.20 (t, 2H), 2.50 (m, 2H), 2.70 (m, 4H),2.80 (m, 2H), 3.60 (m, 5H), 3.90 (s, 3H), 5.00 (s, 2H), 6.80-7.60 (m,14H), 7.90 (d, 2H) 114 (from I and 4- (chloromethyl)-4′- propyl-1,1′-biphenyl by process D)

1.00 (m, 6H), 1.70 (m, 4H), 2.20 (t, 2H), 2.50 (m, 2H), 2.70 (m, 4H),2.80 (m, 2H), 3.60 (s, 2H), 3.90 (s, 3H), 4.00 (q, 2H), 5.00 (s, 2H),6.80-7.60 (m, 14H), 7.90 (d, 2H) 115 (from 114 by process E)

1.00 (t, 3H), 1.70 (m, 4H), 2.20 (t, 2H), 2.50-2.80 (m, 8H), 3.60 (s,2H), 5.00 (s, 2H), 6.80-7.90 (m, 16H) 116 (from 113 by process E)

1.00 (t, 3H), 1.70 (m, 6H), 2.20 (m, 2H), 2.50-2.80 (m, 8H), 3.40 (s,2H), 5.00 (s, 2H), 6.80-7.90 (m, 16H), 12.0 (bs, 2H) 117 (from 112 byprocess E)

1.40 (m, 4H), 2.20 (m, 2H), 2.50-2.80 (m, 6H), 3.40 (s, 2H), 5.00 (s,2H), 6.80-7.90 (m, 17H) 118 (from 111 by process E)

1.60 (m, 4H), 2.20 (t, 2H), 2.50 (s, 3H), 3.20 (m, 6H), 4.20 (s, 2H),5.00 (s, 2H), 6.80-7.60 (m, 11H), 7.90 (d, 2H), 8.10 (d, 2H) 119 (from109 by process E)

1.20 (t, 3H), 2.50 (q, 2H), 3.30 (m, 6H), 4.20 (m, 2H), 4.40 (m, 2H),4.90 (s, 2H), 6.70-8.00 (m, 16H). 120 (from 110 by process E)

1.00 (t, 3H), 1.50 (m, 4H), 2.50 (m, 2H), 3.30 (m, 6H), 4.20 (m, 2H),4.40 (m, 2H), 5.00 (s, 2H), 6.70-8.00 (m, 16H). 121 (from I and 1-(chloromethyl)- 4-[2-(4-fluoro- phenyl)ethyl]- benzene by process D)

1.50 (m, 4H), 2.20 (t, 2H), 2.50 (m, 2H), 2.70 (m, 2H), 2.90 (m, 6H),3.60 (m, 5H), 3.90 (s, 3H), 5.00 (s, 2H), 6.80-7.60 (m, 14H), 7.90 (d,2H) 122 (from IX and 4- methoxybenzyl chloride by process D)

1.40 (t, 3H), 2.90 (m, 6H), 3.70 (s, 3H), 3.80 (s, 2H), 3.95 (m, 5H),4.30 (q, 2H), 4.90 (s, 2H), 6.70-7.40 (m, 12H), 8.00 (m, 4H). 123 (from122 by process E)

3.00 (m, 2H), 3.30 (m, 2H), 3.50 (m, 2H), 3.70 (s, 3H), 4.30 (m, 4H),4.90 (s, 2H), 6.70-7.40 (m, 12H), 8.00 (m, 4H). 124 (from IX and 4-methoxy- ethoxybenzyl chloride by process D)

1.40 (t, 3H), 2.90 (m, 6H), 3.40 (s, 3H), 3.70-4.10 (m, 11H), 4.30 (q,2H), 4.90 (s, 2H), 6.70-7.40 (m, 12H), 8.00 (m, 4H). 125 (from 124 byprocess E)

3.00 (m, 2H), 3.40 (s, 3H), 3.50 (m, 6H), 4.00 (m, 2H), 4.30 (m, 4H),4.90 (s, 2H), 6.70-7.40 (m, 12H), 8.00 (m, 4H). 126 (from 121 by processE)

1.50 (m, 4H), 2.20 (t, 2H), 3.20 (m, 10H), 4.40 (m, 2H), 5.00 (s, 2H),6.80-7.60 (m, 14H), 7.90 (d, 2H) 127 (from IX and 4- butoxybenzylchloride by process D)

1.50 (m, 10H), 2.90 (m, 6H), 3.95 (m, 9H), 4.30 (m, 2H), 4.90 (s, 2H),6.70-7.40 (m, 12H), 8.00 (m, 4H). 128 (from 127 by process E)

1.20 (m, 5H), 1.70 (m, 2H), 3.00 (m, 2H), 3.30 (m, 2H), 3.80 (m, 4H),4.30 (m, 4H), 4.90 (s, 2H), 6.70-7.40 (m, 12H), 8.00 (m, 4H). 129 (fromIX and 4- isopropylbenzyl chloride by process D)

1.20 (d, 6H), 1.40 (t, 3H), 2.70 (m, 7H), 3.80 (s, 2H), 3.95 (m, 5H),4.30 (q, 2H), 4.90 (s, 2H), 6.70-6.90 (m, 4H), 7.10-7.40 (m, 8H), 8.00(m, 4H). 130 (from 129 by process E)

1.20 (d, 6H), 2.70 (m, 1H), 3.30 (m, 6H), 4.20 (m, 2H), 4.40 (m, 2H),4.90 (s, 2H), 6.70-8.00 (m, 16H). 131 (from IX and 4-ethoxybenzylchloride by process D)

1.40 (m, 6H), 2.70 (m, 6H), 3.80 (s, 2H), 3.95 (m, 7H), 4.30 (q, 2H),4.90 (s, 2H), 6.70-6.90 (m, 4H), 7.10-7.40 (m, 8H), 8.00 (m, 4H). 132(from 131 by process E)

1.30 (m, 3H), 2.80 (m, 6H), 4.00 (m, 6H), 4.90 (s, 2H), 6.70-8.00 (m,16H). 133 (from X and 2- (chloromethyl)-1- benzothiophene by process D)

624 (M + 1) 134 (from 133 by process E)

582 (M + 1) 135 (from X and 4- bromobenzyl bromide by process D)

1.70 (m, 4H), 2.20 (t, 2H), 2.50 (m, 2H), 2.80 (m, 4H), 3.60 (m, 5H),3.90 (s, 3H), 5.00 (s, 2H), 6.80-7.60 (m, 10H), 7.90 (d, 2H) 136 (from135 and 4-methylphenyl- boronic acid by process F)

580 (M + 1) 137 (from I and 4- (chloromethyl)- 4′-trifluoro-methoxyphenyl by process D) 1.70 (m, 4H), 2.20 (t, 2H), 2.50 (m, 2H),2.70 (m, 2H), 2.80 (m, 2H), 3.60 (s, 2H), 3.90 (s, 3H), 4.10 (q, 2H),5.00 (s, 2H), 6.80-7.60 (m, 14H), 7.90 (d, 2H) 138 (from 137 by processE)

1.70 (m, 4H), 2.20-3.00 (m, 8H), 3.60 (s, 2H), 5.00 (s, 2H), 6.80-7.90(m, 16H), 12.0 (bs, 2H) 139 (from 135 and 1,3-benzodioxol- 5-yl-boronicacid by process F)

(M + 1), Rt = 3.51³⁾ 140 (from 139 by process E)

582 (M + 1) 141 (from 136 by process E)

552 (M + 1) 142 (from 135 and 4-cyanobenzyl- boronic acid by process F)

591 (M + 1), Rt = 3.42³⁾ 143 (from 142 by process E)

563 (M + 1) 144 (from I and 4- (chloromethyl)-4′- methoxy- ethoxythoxy-phenyl by process D)

1.70 (m, 4H), 2.20 (t, 2H), 2.50 (m, 2H), 2.70 (m, 2H), 2.80 (m, 2H),3.40 (s, 3H), 3.60 (s, 2H), 3.70 (m, 2H), 3.90 (s, 3H), 4.10 (q, 2H),4.20 (m, 2H), 5.00 (s, 2H), 6.80-8.00 (m, 16H) 145 (from 144 by processE)

1.70 (m, 4H), 2.20 (m, 2H), 3.00-3.50 (m, 11H), 3.70 (m, 2H), 4.20 (m,2H), 5.00 (s, 2H), 6.80-7.90 (m, 16) 146 (from 135 and4-trifluoromethyl- phenylboronic acid by process F)

1.60 (m, 4H), 2.20 (t, 2H), 2.50 (m, 2H), 2.70 (m, 2H), 2.80 (m, 2H),3.60 (m, 5H), 3.90 (s, 3H), 5.00 (s, 2H), 6.80-7.60 (m, 14H), 7.90 (d,2H) 147 (from 146 by process E)

1.60 (m, 4H), 2.20 (t, 2H), 3.10 (m, 4H), 3.30 (m, 2H), 4.80 (s, 2H),5.00 (s, 2H), 6.80-7.80 (m, 14H), 8.00 (d, 2H) 148 (from I and 2-[4-(chloro- methyl)phenyl]-5- methylpyridine by process D)

1.20 (t, 3H), 1.60 (m, 4H), 2.20 (t, 2H), 2.40 (s, 3H), 2.50 (m, 2H),2.70 (m, 2H), 2.80 (m, 2H), 3.60 (s, 2H), 3.90 (s, 3H), 4.10 (q, 2H),5.00 (s, 2H), 6.80-7.60 (m, 10H), 7.90 (m, 4H), 8.50 (m, 1H) 149 (from148 by process E)

553 (M + 1), Rt = 2.29 150 (from 135 and 2,4-difluoro- phenylboronicacid by process F)

1.60 (m, 4H), 2.20 (t, 2H), 2.50 (m, 2H), 2.70 (m, 2H), 2.80 (m, 2H),3.60 (m, 5H), 3.90 (s, 3H), 5.00 (s, 2H), 6.80-7.60 (m, 13H), 7.90 (m,2H) 151 (from 150 by process E)

574 (M + 1), Rt = 3.24 152 (from 135 and 4- ethoxyphenyl- boronic acidby process F)

1.60 (m, 7H), 2.20 (t, 2H), 2.50 (m, 2H), 2.70 (m, 2H), 2.80 (m, 2H),3.60 (m, 5H), 3.90 (s, 3H), 4.10 (q, 2H), 5.00 (s, 2H), 6.80-7.60 (m,14H), 7.90 (m, 2H) 153 (from 152 by process E)

1.50 (m, 7H), 2.20 (t, 2H), 3.40 (m), 4.10 (q, 2H), 4.50 (m, 2H), 5.00(s, 2H), 6.70-7.80 (m, 14H), 8.00 (d, 2H) 154 (from 135 and3-cyanophenyl boronic acid by process F)

1.60 (m, 4H), 2.20 (t, 2H), 2.50 (m, 2H), 2.70 (m, 2H), 2.80 (m, 2H),3.60 (m, 5H), 3.90 (s, 3H), 5.00 (s, 2H), 6.70-8.20 (m, 16H) 155 (from154 by process E)

1.50 (m, 4H), 2.20 (m, 2H), 3.40 (m), 4.50 (m, 2H), 5.00 (s, 2H),6.70-2.20 (m, 16H) 156 (from 135 and 3,5-difluoro- phenylboronic acid byprocess F)

1.50 (m, 4H), 2.20 (t, 2H), 2.50 (m, 2H), 2.70 (m, 2H), 2.80 (m, 2H),3.60 (m, 5H), 3.90 (s, 3H), 5.00 (s, 2H), 6.80-7.60 (m, 13H), 7.90 (m,2H) 157 (from 156 by process E)

1.50 (m, 4H), 2.20 (m, 2H), 3.40 (m), 4.50 (m, 2H), 5.00 (s, 2H),6.70-8.20 (m, 15H) 158 (from 135 and 4-tert-butyl- phenylboronic acid byprocess F)

1.40 (s, 9H), 1.50 (m, 4H), 2.20 (t, 2H), 2.50 (m, 2H), 2.70 (m, 2H),2.80 (m, 2H), 3.60 (m, 5H), 3.90 (s, 3H), 5.00 (s, 2H), 6.80-7.60 (m,14H), 7.90 (m, 2H) 159 (from 158 by process E)

1.30 (s, 9H), 1.50 (m, 4H), 2.20 (m, 2H), 3.40 (m), 4.50 (m, 2H), 5.00(s, 2H), 6.70-8.20 (m, 16H) 160 (from 135 and 2,3-difluoro-phenylboronic acid by process F)

602 (M + 1), Rt = 3.56³⁾ 161 (from 160 by process E)

1.50 (m, 4H), 2.00-3.50 (m), 4.50 (m, 2H), 5.00 (s, 2H), 6.70-8.20 (m,15H) 162 (from X and 2-(3- chloropropyl)- 1,3-benzoxazole by process D)

1.40 (t, 3H), 1.50 (m, 6H), 2.20-2.80 (m, 10H), 3.60 (m, 2H), 3.90 (s,3H), 4.10 (m, 4H), 6.80-8.00 (m, 12H) 163 (from 162 by process E)

531 (M + 1), Rt = 2.95³⁾ 164 (from X and 4-tert-butyl-2,6-dimethyl-benzyl chloride by process D)

1.40 (m, 16H), 2.10 (m, 2H), 2.30 (m, 8H), 2.60 (m, 4H), 2.80 (m), 3.50(s, 2H), 3.90 (s, 3H), 4.10 (q, 2H), 5.00 (s, 2H), 6.90-7.40 (m, 8H),7.90 (d, 2H) 165 (from 164 by process E)

1.30 (s, 9H), 1.50 (m, 4H), 2.10 (m, 2H), 2.30 (s, 6H), 2.80 (m), 3.90(s, 2H), 5.00 (s, 2H), 6.90-7.40 (m, 8H), 7.90 (d, 2H) 166 (from X and2-[4- (chloro- methyl)phenyl]- 1,3-benzoxazole by process D)

1.20 (t, 3H), 1.50 (m, 4H), 2.20 (t, 2H), 2.50 (m, 2H), 2.70 (m, 2H),2.80 (m, 2H), 3.60 (s, 2H), 3.90 (s, 3H), 4.10 (q, 2H), 5.00 (s, 2H),6.80-7.80 (m, 12H), 7.90 (d, 2H), 8.10 (d, 2H) 167 (from 166 by processE)

579 (M + 1), Rt = 3.42 168 (from X and 2-(3- chlorobutyl)-1,3-benzoxazole by process D)

587 (M + 1), Rt = 3.44³⁾ 169 (from 168 by process E)

545 (M + 1), Rt = 3.19 170 (from X and (bromomethyl)- cyclohexane byprocess D)

1.00-1.70 (m, 18H), 2.20 (t, 2H), 2.50 (t, 2H), 2.70 (m, 2H), 2.80 (m,2H), 3.70 (m, 4H), 3.80 (s, 3H), 4.10 (q, 2H), 6.80 (m, 2H), 7.20 (m,2H), 7.30 (d, 2H), 7.90 (d, 2H) 171 (from 170 by process E)

1.00 (m, 2H), 1.30 (m, 4H), 1.70 (m, 9H), 2.20 (t, 2H), 2.40 (t, 2H),3.00 (m, 2H), 3.20 (m, 2H), 3.70 (d, 2H), 6.80 (m, 2H), 7.20 (m, 2H),7.60 (d, 2H), 8.10 (d, 2H) 172 (from X and (bromoethyl)- cyclohexane byprocess D)

1.00-1.70 (m, 20H), 2.20 (t, 2H), 2.50 (t, 2H), 2.70 (m, 2H), 2.80 (m,2H), 3.60 (s, 2H), 3.90 (m, 5H), 4.10 (q, 2H), 6.80 (m, 2H), 7.20 (m,2H), 7.30 (d, 2H), 7.90 (d, 2H) 173 (from 172 by process E)

1.00 (m, 2H), 1.20 (m, 2H), 1.40 (m, 1H), 1.70 (m, 10H), 1.90 (m, 2H),2.40 (t, 2H), 3.00 (m, 2H), 3.20 (m, 4H), 4.00 (t, 2H), 4.50 (s, 2H),6.80 (m, 2H), 7.20 (m, 2H), 7.60 (d, 2H), 8.10 (d, 2H) 174 (from X and(bromopropyl)- cyclohexane by process D)

0.80-1.70 (m, 22H), 2.20 (t, 2H), 2.50 (t, 2H), 2.70 (m, 2H), 2.80 (m,2H), 3.60 (s, 2H), 3.90 (m, 5H), 4.10 (q, 2H), 6.80 (m, 2H), 7.20 (m,2H), 7.30 (d, 2H), 7.90 (d, 2H) 175 (from 174 by process E)

1.00 (m, 2H), 1.30 (m, 7H), 1.70 (m, 8H), 1.90 (m, 2H), 2.40 (t, 2H),3.10 (m, 2H), 3.20 (m, 4H), 3.90 (t, 2H), 4.50 (s, 2H), 6.80 (m, 2H),7.20 (m, 2H), 7.60 (d, 2H), 8.10 (d, 2H) 176 (from X and nonyl bromideby process D)

0.80 (t, 3H), 1.20-1.70 (m, 21H), 2.20 (t, 2H), 2.50 (t, 2H), 2.70 (m,2H), 2.80 (m, 2H), 3.60 (s, 2H), 3.90 (m, 5H), 4.10 (q, 2H), 6.80 (m,2H), 7.20 (m, 2H), 7.30 (d, 2H), 7.90 (d, 2H) 177 (from 176 by processE)

0.90 (t, 3H), 1.30 (m, 12H), 1.70 (m, 4H), 1.90 (m, 2H), 2.40 (t, 2H),3.10 (m, 2H), 3.20 (m, 4H), 3.90 (t, 2H), 4.50 (s, 2H), 6.80 (m, 2H),7.20 (m, 2H), 7.60 (d, 2H), 8.10 (d, 2H) 178 (from X and 5-methylhexyl-bromide by process D)

0.90 (d, 6H), 1.10-1.70 (m, 14H), 2.20 (t, 2H), 2.50 (t, 2H), 2.70 (m,2H), 2.80 (m, 2H), 3.60 (s, 2H), 3.90 (m, 5H), 4.10 (q, 2H), 6.80 (m,2H), 7.20 (m, 2H), 7.30 (d, 2H), 7.90 (d, 2H) 179 (from 178 by processE)

0.90 (d, 6H), 1.20 (m, 2H), 1.40 (m, 2H), 1.60 (m, 1H), 1.70 (m, 4H),1.90 (m, 2H), 2.40 (t, 2H), 3.10 (m, 2H), 3.20 (m, 4H), 3.90 (t, 2H),4.50 (s, 2H), 6.80 (m, 2H), 7.20 (m, 2H), 7.60 (d, 2H), 8.10 (d, 2H) 180(from XI and 1- (chloromethyl)-4- (2-phenyl- ethyl)benzene by process D)

1.50 (m, 8H), 2.20 (t, 2H), 2.50 (m, 2H), 2.60-3.00 (m, 8H), 3.60 (s,2H), 4.10 (q, 2H), 4.40 (q, 2H), 5.00 (s, 2H), 6.80-7.60 (m, 14H), 7.60(m, 2H) 181 (from XII and 4-(chloromethyl)- 4′-methoxy- 1,1′-biphenyl byprocess D)

1.00 (m, 4H), 2.20 (t, 2H), 2.50 (m, 2H), 2.70 (m, 4H), 2.80 (m, 2H),3.60 (m, 5H), 3.90 (s, 3H), 3.95 (s, 3H), 5.00 (s, 2H), 6.80-7.00 (m,5H), 7.40 (m, 4H), 7.50 (m, 4H), 7.90 (d, 2H) 182 (from 181 by processE)

1.60 (m, 4H), 2.20 (t, 2H), 3.00 (m, 6H), 3.80 (s, 3H), 4.20 (s, 2H),5.00 (s, 2H), 6.80-7.00 (m, 5H), 7.50 (m, 8H), 8.00 (d, 2H) 183 (fromXIII and methyl 5-bromo- valerateanalogously to I.2)

1.50 (m, 13H), 2.20 (t, 2H), 2.50 (m, 2H), 2.60-3.00 (m, 8H), 3.60 (m,5H), 4.40 (q, 2H), 5.00 (s, 2H), 6.80-7.60 (m, 15H), 7.80 (m, 2H) 184(from 183 using trifluoroacetic acid)

580 (M + 1), Rt = 3.87¹⁾NMR conditions: d6-DMSO, 300 MHz²⁾LC/MS conditions: column: Symmetry C18 2.1 * 150 mm; mobile phaseacetonitrile/0.6 g of HCl 30% strength/H₂O; gradient: 10% acetonitrileto 90% acetonitrile; flow rate: 0.6 ml/min; detector: UV 210 nm³⁾LC/MS conditions: column: Symmetry C18 2.1 * 150 mm; mobile phase:acetonitrile/H₂O (0.1% formic acid); gradient: 10% acetonitrile to 90%acetonitrile; flow rate: 0.5 ml/min; detector: UV 210 nm

Example 185 Methyl4-{[(2-{5-fluoro-2-[(4′-methyl-1,1′-biphenyl-4-yl)methoxy]phenyl}ethyl)(5-methoxy-5-oxopentyl)amino]methyl}benzoate

447 mg (0.93 mmol) of methyl4-({(5-methoxy-5-oxopentyl)[2-(5-fluoro-2-hydroxyphenyl)ethyl]amino}methyl)benzoatefrom Ex. XII and 277 mg (1.02 mmol) of4-(chloromethyl)-4′-(trifluoromethyl)-1,1′-biphenyl are dissolved in 10ml of acetonitrile. 455 mg (1.40 mmol) of caesium carbonate and aspatula tip of potassium iodide are added, and the mixture is heated atreflux for 48 hours. The suspension is filtered and concentrated and theresidue is chromatographed over silica gel using cyclohexane:ethylacetate (5:1).

Yield: 447 mg (73.6% of theory)

¹H-NMR (d6-DMSO, 300 MHz): 1.00 (m, 4H), 2.20 (t, 2H), 2.50 (m, 2H),2.70 (m, 4H), 2.80 (m, 2H), 3.60 (m, 5H), 3.90 (s, 3H), 5.00 (s, 2H),6.80-7.00 (m, 3H), 7.30 (d, 4H), 7.40 (d, 2H), 7.50 (d, 2H), 7.70 (m,4H), 7.90 (d, 2H).

Example 1864-{[(4-Carboxybutyl)(2-{5-fluoro-2-[(4′-methyl-1,1′-biphenyl-4-yl)-methoxy]phenyl}ethyl)amino]methyl}benzoicacid

0.45 g (0.69 mmol) of methyl4-{[(2-{5-fluoro-2-[(4′-methyl-1,1′-biphenyl-4-yl)methoxy]phenyl}ethyl)(5-methoxy-5-oxopentyl)amino]methyl}benzoatefrom Ex. 185 is dissolved in 8 ml of methanol. 0.5 ml of aqueous sodiumhydroxide solution (45%) and 1.5 ml of dichloromethane are added, andthe solution is stirred at RT for 8 hours. The reaction is extractedwith diethyl ether, the aqueous phase is acidified using sulphuric acidand extracted with ethyl acetate and the extract is filtered throughExtrelut and concentrated.

Yield: 245 mg (57.3% of theory)

¹H-NMR: (300 MHz, MeOD): 1.60 (m, 4H), 2.20 (t, 2H), 3.00 (m, 4H), 3.20(m, 2H), 4.20 (s, 2H), 5.10 (s, 2H), 7.00 (m, 3H), 7.50 (m, 4H), 7.70(m, 6H), 7.90 (d, 2H).

Example 187 Methyl4-{[(5-ethoxy-5-oxopentyl)(2-{[5-(4-phenylpiperazino)-pentyl]oxy}phenethyl)amino]methyl}benzoate

200.0 mg (0.355 mmol) of methyl4-{[{2-[(5-bromopentyl)oxy]phenethyl}(5-ethoxy-5-oxopentyl)amino]methyl}benzoatefrom Ex. 107, 69.21 mg of N-phenylpiperazine and 71.95 mg (0.711 mmol)of triethylamine in 2 ml of tetrahydrofuran are heated at reflux for 18hours. The reaction solution is washed with water, concentrated andchromatographed over silica gel using the mobile phase ethylacetate/methanol 10/1.

Yield: 66.0 mg (28.83% of theory)

¹H-NMR (300 MHz, d⁶-DMSO): δ=1.12 (t, 3H), 1.44 (m, 8H), 1.65 (m, 2H),2.35 (m, 4H), 2.45 (m, 4H), 2.55 (m, 2H), 2.72 (m, 2H), 3.10 (m, 4H),3.65 (s, 2H), 3.85 (s, 3H), 3.88 (t, 2H), 4.05 (m, 2H), 6.70-6.90 (m,5H), 7.0-7.2 (m, 4H), 7.4 (d, 2H), 7.8 (d, 2H).

The following compounds can be obtained analogously: Physical data:¹H-NMR (δ in ppm, selection)¹⁾ or LC/MS Example Structure(mass/retention time [min])²⁾ 188 (from 107 and N-(4-chloro- phenyl)-piperazine

679 (M + 1), Rt = 3.60 189 (from 108 and N-phenyl- piperazine

602 (M + 1), Rt = 3.60 190 (from 187 by process E)

601 (M + 1), Rt = 2.43 191 (from 188 by process E)

635 (M + 1), Rt = 2.58 192 (from 189 by process E)

559 (M + 1), Rt = 2.11 193 (from I and 1,3- dibromo- propane by processD)

1.50 (m, 4H), 2.40 (m, 4H), 2.70 (m, 6H), 3.50 (m, 2H), 3.60 (m, 5H),3.90 (s, 3H), 4.00 (t, 2H), 6.80-7.40 (m, 6H), 7.90 (d, 2H) 194 (from Iand 1,3- dibromobutane by process D)

1.50 (m, 4H), 1.90 (m, 4H), 2.20 (t, 2H), 2.50 (t, 2H), 2.70 (m, 4H),3.40 (m, 2H), 3.60 (m, 5H), 3.90 (m, 5H), 6.80-7.40 (m, 6H), 7.90 (d,2H) 195 (from 193 and N-phenyl- piperazine

1.50 (m, 4H), 1.90 (m, 2H), 2.40 (t, 2H), 2.70 (m, 8H), 3.10 (m, 8H),3.60 (m, 5H), 3.90 (s, 3H), 4.00 (t, 2H), 6.80-7.40 (m, 11H), 7.90 (d,2H) 196 (from 195 by process E)

574 (M + 1) 197 (from 194 and N- 2-pyrimi- dinepiperazine and by processE)

1.50-2.80 (m, 20H), 3.60 (s, 2H), 3.80 (m, 6H), 4.00 (t, 2H), 6.50-7.40(m, 7H), 7.90 (d, 2H), 8.20 (d, 2H) 198 (from 194 and N- phenyl-piperazine

1.50 (m, 8H), 2.20 (t, 2H), 2.70 (m, 12H), 3.10 (m), 3.60 (m, 5H), 4.00(m, 5H), 6.80-7.40 (m, 11H), 7.90 (d, 2H) 199 (from 198 by process E)

1.50 (m, 8H), 2.20 (t, 2H), 2.80-2.50 (m, 12H), 3.20 (m, 4H), 3.80 (s,2H), 4.00 (t, 2H), 6.80-7.40 (m, 11H), 7.90 (d, 2H) 200 (from 193 andN-2-methyl- phenylpiper- azine

1.50-3.20 (m), 3.60 (m, 5H), 4.00 (m, 5H), 6.80-7.40 (m, 10H), 7.90 (d,2H) 201 (from 200 by process E)

1.50 (m, 6H), 2.20 (m, 5H), 2.80-2.50 (m), 3.20 (m), 3.60 (s, 2H), 4.00(t, 2H), 6.80-7.40 (m, 10H), 7.90 (d, 2H) 202 (from 194 and piperidine)

1.50 (m, 14H), 2.80-2.10 (m, 14H), 3.60 (m, 5H), 3.90 (m, 5H), 6.80-7.40(m, 6H), 7.90 (d, 2H) 203 (from 202 by process E)

1.50 (m, 14H), 2.80-2.10 (m, 14H), 3.60 (s, 2H), 3.90 (t, 2H), 6.80-7.40(m, 6H), 7.90 (d, 2H) 204 (from IX and 1,3- dibromo- propane by processD)

1.30 (t, 3H), 2.20 (m, 2H), 2.80 (m, 4H), 3.00 (t, 2H), 3.50 (t, 2H),3.80 (s, 2H), 3.90 (s, 3H), 4.00 (m, 4H), 4.30 (q, 2H), 6.80-7.40 (m,8H), 8.00 (m, 4H). 205 (from 204 and N- 2-methyl- phenylpipera- zine andby process E)

652 (M + 1), Rt = 2.53³⁾ 206 (from 204 and N- phenyl- piperazine and byprocess E)

638 (M + 1), Rt = 2.39³⁾ 207 (from 204 and N- 4-trifluoro- methylphenyl-piperazine)

1.30 (t, 3H), 1.90 (m, 2H), 2.50 (m, 6H), 2.90 (m, 6H), 3.20 (m, 4H),4.00 (m, 9H), 4.30 (q, 2H), 6.80-7.40 (m, 12H), 8.00 (m, 4H). 208 (from207 by process E)

706 (M + 1), Rt = 2.64³⁾ 209 (from 204 and N-2,4-di fluorophenyl-piperazine)

1.30 (t, 3H), 1.90 (m, 2H), 2.50 (m, 6H), 2.80 (s, 4H), 3.00 (m, 6H),4.00 (m, 9H), 4.30 (q, 2H), 6.80-7.40 (m, 11H), 8.00 (m, 4H). 210 (from209 by process E)

674 (M + 1); Rt = 2.60²⁾¹⁾NMR conditions: d6-DMSO, 300 MHz²⁾LC/MS conditions: column: Symmetry C18 2.1 * 150 mm; mobile phase:acetonitrile/0.6 g of HCl 30% strength/H₂O; gradient: 10% acetonitrileto 90% acetonitrile; flow rate: 0.6 ml/min; detector: UV 210 nm³⁾LC/MS conditions: column: Symmetry C18 2.1 * 50 mm; mobile phase:acetonitrile/H₂O (0.1% formic acid); gradient: 10% acetonitrile to 90%acetonitrile; flow rate: 0.5 ml/min; detector: UV 210 min

211: Methyl6-{[{2-[2-(1,1′-biphenyl-4-ylmethoxy)phenyl]ethyl}(5-tert-butoxy-5-oxopentyl)-amino]methyl}nicotinate

A solution of 132.0 mg (0.29 mmol) of XXa in 3 ml of DMF was admixedwith 198.5 mg (1.44 mmol) of potassium carbonate, 121.1 mg (0.32 mmol)of methyl-6-(bromomethyl)nicotinate and a catalytic amount of KI. Themixture was stirred at room temperature for 16 h and the reaction wasmonitored by thin-layer chromatography. The solution was admixed withwater and extracted with ethyl acetate/cyclohexane 1:1. The combinedorganic phases were dried over Na₂SO₄ and the solvent was removed. Theproduct was purified chromatographically (silica gel, cyclohexane/ethylacetate 10:1).

Yield: 55.8%

¹H-NMR (300 MHz, CDCl₃): δ=1.16-1.58 (m, 4H), 1.40 (s, 9H), 2.11 (t,J=7.2 Hz, 2H), 2.54 (t, J=6.4 Hz, 2H), 2.70-2.81 (m, 2H), 2.82-2.92 (m,2H), 3.81 (s, 2H), 3.89 (s, 3H), 5.04 (s, 2H), 6.82-7.62 (m, 14H),8.04-8.17 (m, 1H), 9.02-9.08 (m, 1H).

The following compounds were prepared analogously: Physical data: ¹H-NMR(δ in ppm, Yield selection)¹⁾ or LC/MS Example Structure (%)(mass/retention time [min])²⁾ 212 (from XXa and 2- methoxy- carbonyl-benzyl chloride

66.4 ¹H-NMR (300 MHz, CDCl₃): δ=1.39 (s, 9H), 1.45-1.52 (m, 4H), 2.07(t, J=7.4 Hz, 2H), 2.47 (t, J=6.6.Hz, 2H), 2.65-2.75 (m, 2H), 2.77-2.87(m, 2H), 3.81 (s, 3H), 3.90 (s, 2H), 5.05 (s, 2H), 6.78-7.80 (m, 17H).213 (from XXa and 3- t-butoxy- carbonyl- benzyl chloride

85.5 ¹H NMR (300 MHz, CDCl₃): δ=1.35-1.64 (m, 4H), 1.40 (s, 9H), 1.57(s, 9H), 2.10 (t, J=7.2 Hz, 2H), 2.47 (t, J=6.4 Hz, 2H), 2.66-2.76 (m,2H), 2.79-2.91 (m, 2H), 3.63 (s, 2H), 5.05 (s, 2H), 6.80-7.92 (m, 17H).214 (from XXa and 2- methoxy-4- methoxy- carbonyl- benzyl chloride

42.8 ¹H NMR (300 MHz, CDCl₃): δ=1.31-1.57 (m, 4H), 1.40 (s, 9H), 2.11(t, J=7.0 Hz, 2H), 2.51 (t, J=7.0 Hz, 2H), 2.68-2.78 (m, 2H), 2.81-2.92(m, 2H), 3.66 (s, 2H), 3.80 (s, 3H), 3.87 (s, 3H), 5.05 (s, 2H),6.81-7.64 (m, 16H). 215 (from XXa and 3- methoxy-4- methoxy- carbonyl-benzyl chloride

55.6 ¹H NMR (300 MHz, CDCl₃): δ=1.34-1.61 (m, 4H), 1.40 (s, 9H),2.03-2.16 (m, 2H), 2.35-2.55 (m, 2H), 2.64-2.76 (m, 2H), 2.77-2.93 (m,2H), 3.59 (s, 2H), 3.79 (s, 3H), 3.84 (s, 3H), 5.04 (s, 2H), 6.73-7.73(m, 16H). 216 (from XXa and 4- methoxy- carbonyl- methyl- benzylchloride

57.7 ¹H NMR (300 MHz, CDCl₃): δ=1.34-1.59 (m, 4H), 1.40 (s, 9H), 2.11(t, J=7.0 Hz, 2H), 2.46 (t, J=7.0 Hz, 2H), 2.62-2.74 (m, 2H), 2.78-2.90(m, 2H), 3.56 (s, 2H), 3.58 (s, 2H), 3.65 (s, 3H), 5.05 (s, 2H),6.80-7.64 (m, 17H). 217 (from XXb and 4- methoxy- carbonyl- benzylchloride

50.1 LC/MS: 4.52 min, m/z = 614 (M + 1).

218:5-{{2-[2-(1,1′-Biphenyl-4-ylmethoxy)phenyl]ethyl}[2-methoxy-4-(methoxy-carbonyl)-benzyl]-amino}pentanoicacid hydrochloride

A solution of 96.7 mg (0.15 mmol) of the compound from Ex. 214 in 3 mlof dioxane was mixed with 5 ml of 1 M HCl in dioxane. The mixture wasstirred at room temperature and the reaction was monitored by thin-layerchromatography. After the reaction had ended, the solvent was removedand the product was purified chromatographically (silica gel,CH₂Cl₂/MeOH 10: 1).

Yield: 51.8 mg (55.2%)

¹H NMR (400 MHz, DMSO-d₆): δ=1.37-1.49 (m, 2H), 1.59-1.80 (m, 2H),2.03-2.26 (m, 2H), 2.95-3.37 (m, 6H), 3.83 (s, 3H), 3.87 (s, 3H), 4.34(s, 2H) 5.15 (s, 2H), 6.82-7.77 (m, 16H), 9.45 (bs, 1H), 12.08 (bs, 1H).

The following compounds were prepared in an analogous manner, wherefurther hydrolysis of the monoester was achieved in the followingmanner:

A mixture of 0.078 mmol of monoester, 1 ml of water, 200 μl of 45%strength NaOH and 2 ml of dioxane was stirred at room temperature for 16h. The mixture was acidified with 1 N HCl and the solvent was removed.The residue was taken up in ethanol and the sodium chloride formed wasfiltered off. The product was purified chromatographically (preparativethin-layer chromatography, EtOH). Physical data: ¹H-NMR (δ in ppm, Yieldselection)¹⁾ or LC/MS Example Structure (%) (mass/retention time[min])²⁾ 219 (from XXa and ethyl 5- bromo- pentanoate analogously to 211and 218)

69.4 ¹H NMR (300 MHz, DMSO-d₆): δ=1.38-1.77 (m, 8H), 2.21-2.35 (m, 4H),3.02-3.26 (m, 6H), 3.27-3.60 (m, 2H), 5.02 (s, 2H), 6.64-7.69 (m, 13H),9,14 (bs, 1H), 12.10 (bs, 2H). 220 (from 212)

77.3 LC/MS: 3.61 min [m/z = 552 (M + H)] 221 (from 213)

39.8 ¹H NMR (400 MHz, DMSO-d₆): δ=1.42 (t, J=7.3 Hz, 2H), 1.58-1.86 (m,2H), 2.15 (t, J=7.3 Hz, 2H), 2.86-3.25 (m, 7H), 4.45 (s, 2H), 5.14 (s,2H), 6.67-8.33 (m, 17H), 12.18 (bs, 1H), 13.12 (bs, 1H). 222 (from 211)

44.6 ¹H NMR (400 MHz, DMSO-d₆): δ=1.38-1.49 (m, 2H), 1.62-1.75 (m, 2H),2.17 (t, J=7.3 Hz, 2H), 3.01-3.11 (m, 2H), 3.12-3.21 (m, 2H), 3.22-3.46(m, 3H), 3.84 (s, 3H), 4.62 (s, 2H), 5.14 (s, 2H), 6.82-8.39 (m, 16H),9.08 (bs, 1H). 223 (from 215)

32.8 ¹H NMR (400 MHz, DMSO-d₆): δ=1.28-1.53 (m, 2H), 1.60-1.83 (m, 2H),2.08-2.25 (m, 2H), 2.93-3.39 (m, 6H), 3.75 (s, 3H), 3.87 (s, 3H), 4.39(s, 2H), 5.15 (s, 2H), 6.77-7.80 (m, 16H), 10.26 (bs, 1H), 12.11 (bs,1H). 224 (from 216)

48.8 ¹H NMR (400 MHz, DMSO-d₆): δ=1.34-1.51 (m, 2H), 1.58-1.80 (m, 2H),2.16 (t, J=7.4 Hz, 2H), 2.91-3.23 (m, 6H), 3.58 (s, 3H), 3.68 (s, 2H),4.33 (s, 2H), 5.15 (s, 2H), 6.82-7.77 (m, 17H), 10.12 (bs, 1H), 12.11(bs, 1H). 225 (from XXa and 4- methoxy- carbonyl- benzyl chlorideanalogously to 211 and 218

70.0 ¹H NMR (400 MHz, DMSO-d₆): δ=1.36-1.52 (m, 2H), 1.59-1.79 (m, 2H),2.04-2.24 (m, 2H), 2.89-3.26 (m, 6H), 3.81 (s, 3H), 4.43 (s, 2H), 5.14(s, 2H), 6.76-8.13 (m, 17H), 10.24 (bs, 1H), 12.09 (bs, 1H). 226 (from216)

100 LC/MS = 4.09 min, m/z = 552 (M + H). 227 (from 212)

76.9 LC/MS = 3.60 min, m/z = 538 (M + H). 228 (from 211)

78.9 LC/MS = 3.29 min, m/z = 539 (M + H). 229 (from 214)

76.2 LC/MS = 3.42 min, m/z = 568 (M + H). 230 (from 215)

79.2 LC/MS = 3.32 min, m/z = 568 (M + H). 231 (from 217)

76.2 LC/MS = 3.99 min, m/z = 558 (M + H).

232:4-[((4-carboxybutyl){2-[2-({4-[2-(4-hydroxyphenyl)ethyl]benzyl}oxy)phenyl]-ethyl}amino)methyl]benzoicacid

27 mg (0.037 mmol) of methyl4-{[{2-[2-({4-[2-(4-{[tert-butyl(dimethyl)-silyl]oxy}phenyl)ethyl]benzyl}oxy)phenyl]ethyl}(5-ethoxy-5-oxopentyl)amino]-methyl}benzoatefrom XXI are dissolved in 10 ml of THF. 0.03 ml of tetrabutylammoniumfluoride (1M solution in THF) are added, and the solution is stirred atRT for 1 hour. The solvents are evaporated under reduced pressure. Theresidue is dissolved in 2 ml of methanol. 0.05 ml of aqueous sodiumhydroxide solution, 45%, and 0.2 ml of dichloromethane are added, andthe solution is stirred at RT for 8 hours. The mixture is concentrated,water is added and the solution is acidified using sulphuric acid. Thesolid is filtered off and dried.

Yield: 20 mg (93% of theory)

¹H-NMR (300 MHz, MeOD): δ=1.45 (m, 4H), 2.30 (t, 2H), 2.80 (m, 4H),3.00-3.40 (m), 4.80 (s, 2H), 5.00 (s, 2H), 6.60 (m, 2H), 6.90-7.30(10H), 7.50 (d, 2H), 8.00 (d, 2H).

1. A compound of the general formula (I)

in which V is absent, O, NR⁴, NR⁴CONR⁴, NR⁴CO, NR⁴SO₂, COO, CONR⁴ orS(O)_(o), in which R⁴, independently of any other radical R⁴ which maybe present, is hydrogen, straight-chain or branched alkyl having up to 8carbon atoms, cycloalkyl having 3 to 8 carbon atoms, aryl having 6 to 10carbon atoms or arylalkyl having 7 to 18 carbon atoms, where the arylradical for its part may be mono- or polysubstituted by halogen, alkyl,alkoxy having up to 6 carbon atoms, o is 0, 1 or 2, Q is absent,straight-chain or branched alkylene, straight-chain or branchedalkenediyl or straight-chain or branched alkynediyl, having in each caseup to 12 carbon atoms, which may in each case contain one or more groupsselected from the group consisting of O, S(O)_(p), NR⁵, CO, NR⁵SO₂ andCONR⁵ and which may be mono- or polysubstituted by halogen, hydroxyl oralkoxy having up to 4 carbon atoms, where optionally any two atoms ofthe abovementioned chain may be attached to one another forming a three-to eight-membered ring, in which R⁵ is hydrogen, straight-chain orbranched alkyl having up to 8 carbon atoms or cycloalkyl having 3 to 8carbon atoms, which may be substituted by halogen or alkoxy having up to4 carbon atoms, and p is 0, 1 or 2, Y is hydrogen, NR⁸R⁹, aryl having 6to 10 carbon atoms, an aromatic or saturated heterocycle having 1 to 9carbon atoms and up to 3 heteroatoms selected from the group consistingof S, N and O, or straight-chain or branched cycloalkyl having 3 to 8carbon atoms, which may also be attached via N, wherein the cyclicradicals may in each case be mono- to trisubstituted by straight-chainor branched alkyl, straight-chain or branched alkenyl, straight-chain orbranched alkynyl, straight-chain or branched alkoxy, straight-chain orbranched halogenoalkyl, straight-chain or branched halogenoalkoxy havingin each case up to 8 carbon atoms, straight-chain or branched cycloalkylhaving 3 to 8 carbon atoms, halogen, hydroxyl, CN, SR⁶, NO₂, NR⁸R⁹,NR⁷COR¹⁰, NR⁷CONR⁷R¹⁰ or CONR¹¹R¹², in which R⁶ is hydrogen,straight-chain or branched alkyl having up to 8 carbon atoms,straight-chain or branched halogenoalkyl having up to 8 carbon atoms orcycloalkyl having 3 to 8 carbon atoms, R⁷ independently of any otherradical R⁷ which may be present is hydrogen, straight-chain or branchedalkyl having up to 8 carbon atoms or cycloalkyl having 3 to 8 carbonatoms, R⁸, R⁹, R¹¹ and R¹² independently of one another are hydrogen,straight-chain or branched alkyl, straight-chain or branched alkenylhaving up to 8 carbon atoms, aryl having 6 to 10 carbon atoms, anaromatic heterocycle having 1 to 9 carbon atoms and up to 3 heteroatomsselected from the group consisting of S, N and O, arylalkyl having 8 to18 carbon atoms, cycloalkyl having 3 to 8 carbon atoms or a radical ofthe formula SO₂R¹³, wherein the aryl radical for its part may be mono-or polysubstituted by halogen, hydroxyl, CN, NO₂, NH₂, NHCOR⁷, alkyl,alkoxy, halogenoalkyl or halogenoalkoxy having up to 6 carbon atoms, ortwo substituents R⁸ and R⁹ or R¹¹ and R¹² may be attached to one anotherforming a five- or six-membered ring which may contain O or N, andwherein R¹³ is straight-chain or branched alkyl having up to 4 carbonatoms or aryl having 6 to 10 carbon atoms, where the aryl radical forits part may be mono- or polysubstituted by halogen, CN, NO₂, alkyl,alkoxy, halogenoalkyl or halogenoalkoxy having up to 6 carbon atoms, R¹⁰is hydrogen, straight-chain or branched alkyl having up to 12 carbonatoms, straight-chain or branched alkenyl having up to 12 carbon atoms,aryl having 6 to 10 carbon atoms, an aromatic heterocycle having 1 to 9carbon atoms and up to 3 heteroatoms selected from the group consistingof S, N and O, or cycloalkyl having 3 to 8 carbon atoms, which mayfurthermore optionally be substituted by halogen, hydroxyl, CN, NO₂,NH₂, NHCOR⁷, alkyl, alkoxy, halogenoalkyl or halogenoalkoxy having up to6 carbon atoms; and/or the cyclic radicals in Y may in each case bemono- to trisubstituted by aryl having 6 to 10 carbon atoms, or by anaromatic or saturated heterocycle having 1 to 9 carbon atoms and up to 3heteroatoms selected from the group consisting of S, N and O, which mayalso be attached via N, which may be attached directly or via a group O,S, SO, SO₂, NR⁷, SO₂NR⁷, CONR⁷, straight-chain or branched alkylene,straight-chain or branched alkenediyl, straight-chain or branchedalkyloxy, straight-chain or branched oxyalkyloxy, straight-chain orbranched sulphonylalkyl, straight-chain or branched thioalkyl having ineach case up to 8 carbon atoms and which may be mono- to trisubstitutedby straight-chain or branched alkyl, straight-chain or branched alkoxy,straight-chain or branched alkoxyalkoxy, straight-chain or branchedhalogenoalkyl, straight-chain or branched halogenoalkoxy, carbonylalkylor straight-chain or branched alkenyl having in each case up to 6 carbonatoms, halogen, SR⁶, CN, NO₂, NR⁸R⁹, CONR¹⁵R¹⁶ or NR¹⁴COR¹⁷, in whichR¹⁴ is hydrogen, straight-chain or branched alkyl having up to 8 carbonatoms or cycloalkyl having 3 to 8 carbon atoms, R¹⁵, R¹⁶ independentlyof one another are hydrogen, straight-chain or branched alkyl having upto 8 carbon atoms, cycloalkyl having 3 to 8 carbon atoms, aryl having 6to 10 carbon atoms or a radical of the formula SO₂R¹⁸, where the arylradical for its part may be mono- or polysubstituted by halogen,hydroxyl, CN, NO₂, NH₂, NHCOR⁷, alkyl, alkoxy, halogenoalkyl orhalogenoalkoxy having up to 6 carbon atoms, in which R¹⁸ isstraight-chain or branched alkyl having up to 4 carbon atoms or arylhaving 6 to 10 carbon atoms, where the aryl radical for its part may bemono- or polysubstituted by halogen, hydroxyl, CN, NO₂, NH₂, NHCOR⁷,alkyl, alkoxy, halogenoalkyl or halogenoalkoxy having up to 6 carbonatoms, and R¹⁷ is hydrogen, straight-chain or branched alkyl having upto 12 carbon atoms, straight-chain or branched alkenyl having up to 12carbon atoms, aryl having 6 to 10 carbon atoms, an aromatic heterocyclehaving 1 to 9 carbon atoms and up to 3 heteroatoms selected from thegroup consisting of S, N and O, or cycloalkyl having 3 to 8 carbonatoms, which may furthermore optionally be substituted by halogen,hydroxyl, CN, NO₂, NH₂, NHCOR⁷, alkyl, alkoxy, halogenoalkyl orhalogenoalkoxy having up to 6 carbon atoms; and/or the cyclic radicalsin Y may be fused with an aromatic or saturated carbocycle having 1 to10 carbon atoms or an aromatic or saturated heterocycle having 1 to 9carbon atoms and up to 3 heteroatoms selected from the group consistingof S, N and O, R³ is hydrogen, halogen, straight-chain or branchedalkyl, straight-chain or branched halogenoalkyl, straight-chain orbranched alkoxy, or alkoxycarbonyl having in each case up to 4 carbonatoms, or CN, NO₂ or NR¹⁹R²⁰, in which R¹⁹ and R²⁰ independently of oneanother are hydrogen, straight-chain or branched alkyl having up to 4carbon atoms or cycloalkyl having 3 to 8 carbon atoms, m is an integerfrom 1 to 4, W is straight-chain or branched alkylene having up to 6carbon atoms or straight-chain or branched alkenediyl having up to 6carbon atoms, which may in each case contain a group selected from thegroup consisting of O, S(O)_(q), NR²¹, CO and CONR²¹, or is CO, NHCO orOCO, in which q is0, 1 or 2, R²¹ is hydrogen, straight-chain or branchedalkyl having up to 8 carbon atoms or cycloalkyl having 3 to 8 carbonatoms, U is straight-chain or branched alkyl having up to 4 carbonatoms, A is aryl having 6 to 10 carbon atoms or an aromatic heterocyclehaving 1 to 9 carbon atoms and up to 3 heteroatoms selected from thegroup consisting of S, N and O, which may optionally be mono- totrisubstituted by halogen, straight-chain or branched alkyl,straight-chain or branched halogenoalkyl, straight-chain or branchedalkoxy, halogenoalkoxy or alkoxycarbonyl having up to 4 carbon atoms,CN, NO₂ or NR²²R²³, in which R²² and R²³ independently of one anotherare each hydrogen, straight-chain or branched alkyl having up to 8carbon atoms or cycloalkyl having 3 to 8 carbon atoms, carbonylalkyl orsulphonylalkyl, R² is tetrazolyl, COOR²⁴ or CONR²⁵R²⁶, in which R²⁴ ishydrogen, alkyl having 1 to 8 carbon atoms or cycloalkyl having 3 to 8carbon atoms, R²⁵ and R²⁶ independently of one another are eachhydrogen, straight-chain or branched alkyl having up to 8 carbon atoms,cycloalkyl having 3 to 8 carbon atoms or a radical of the formulaSO₂R²⁷, or R²⁵ and R²⁶ together form a five- or six-membered ring whichmay contain N or O, in which R²⁷ is straight-chain or branched alkylhaving up to 4 carbon atoms or aryl having 6 to 10 carbon atoms, wherethe aryl radical for its part may be mono- or polysubstituted byhalogen, CN, NO₂, alkyl, alkoxy, halogenoalkyl or halogenoalkoxy havingup to 6 carbon atoms, X is straight-chain or branched alkylene having upto 12 carbon atoms or straight-chain or branched alkenediyl having up to12 carbon atoms which may in each case contain one to three groupsselected from the group consisting of O, S(O)_(r), NR²⁸, CO and CONR²⁹,or is aryl or aryloxy having 6 to 10 carbon atoms, where the arylradical for its part may be mono- or polysubstituted by halogen, CN,NO₂, alkyl, alkoxy, halogenoalkyl or halogenoalkoxy having up to 6carbon atoms, where optionally any two atoms of the abovementionedchains are attached to one another via an alkyl chain, forming a three-to eight-membered ring, in which r is 0, 1 or 2, R²⁸ is hydrogen, alkylhaving 1 to 8 carbon atoms or cycloalkyl having 3 to 8 carbon atoms, R²⁹is hydrogen, straight-chain or branched alkyl having up to 8 carbonatoms or cycloalkyl having 3 to 8 carbon atoms, n is 1 or 2; and R¹ istetrazolyl, COOR³⁰ or CONR³¹R³², in which R³⁰ is hydrogen, alkyl having1 to 8 carbon atoms or cycloalkyl having 3 to 8 carbon atoms, R³¹ andR³² independently of one another are each hydrogen, straight-chain orbranched alkyl having up to 8 carbon atoms, cycloalkyl having 3 to 8carbon atoms or a radical of the formula SO₂R³³, in which R³³ isstraight-chain or branched alkyl having up to 4 carbon atoms or arylhaving 6 to 10 carbon atoms, where the aryl radical for its part may bemono- or polysubstituted by halogen, CN, NO₂, alkyl, alkoxy,halogenoalkyl or halogenoalkoxy having up to 6 carbon atoms, and itsstereoisomers and salts.


2. A compound of the formula (II)

in which V is absent, O, NR⁴, NR⁴CONR⁴, NR⁴CO, NR⁴SO₂, COO, CONR⁴ orS(O)_(o), in which R⁴, independently of any other radical R⁴ which maybe present, is hydrogen, straight-chain or branched alkyl having up to 8carbon atoms, cycloalkyl having 3 to 8 carbon atoms, aryl having 6 to 10carbon atoms or arylalkyl having 7 to 18 carbon atoms, where the arylradical for its part may be mono- or polysubstituted by halogen, alkyl,or alkoxy having up) to 6 carbon atoms, o is 0, 1 or 2, Q is absent,straight-chain or branched alkylene, straight-chain or branchedalkenediyl or straight-chain or branched alkynediyl, having in each caseup to 12 carbon atoms, which may in each case contain one or more groupsselected from the group consisting of O, S(O)_(p), NR⁵, CO, NR⁵SO₂ andCONR⁵ and which may be mono- or polysubstituted by halogen, hydroxyl oralkoxy having up to 4 carbon atoms, where optionally any two atoms ofthe abovementioned chain may be attached to one another forming a three-to eight-membered ring. in which R⁵ is hydrogen, straight-chain orbranched alkyl having up to 8 carbon atoms or cycloalkyl having 3 to 8carbon atoms, which may be substituted by halogen or alkoxy having up to4 carbon atoms, and p is 0, 1 or 2, Y is hydrogen, NR⁸R⁹, aryl having 6to 10 carbon atoms, an aromatic or saturated heterocycle having 1 to 9carbon atoms and up to 3 heteroatoms selected from the group consistingof S, N and O, or straight-chain or branched cycloalkyl having 3 to 8carbon atoms, which may also be attached via N, wherein the cyclicradicals may in each case be mono- to trisubstituted by straight-chainor branched alkyl, straight-chain or branched alkenyl, straight-chain orbranched alkynyl, straight-chain or branched alkoxy, straight-chain orbranched halogenoalkyl, straight-chain or branched halogenoalkoxy havingin each case up to 8 carbon atoms, straight-chain or branched cycloalkylhaving 3 to 8 carbon atoms, halogen, hydroxyl, CN, SR⁶, NO₂, NR⁸R⁹,NR⁷COR¹⁰, NR⁷CONR⁷R¹⁰ or CONR¹¹R¹², in which R⁶ is hydrogen,straight-chain or branched alkyl having up to 8 carbon atoms,straight-chain or branched halogenoalkyl having up to 8 carbon atoms orcycloalkyl having 3 to 8 carbon atoms, R⁷ independently of any otherradical R⁷ which may be present is hydrogen, straight-chain or branchedalkyl having up to 8 carbon atoms or cycloalkyl having 3 to 8 carbonatoms, R⁸, R⁹, R¹¹ and R¹² independently of one another are hydrogen,straight-chain or branched alkyl, straight-chain or branched alkenylhaving up to 8 carbon atoms, aryl having 6 to 10 carbon atoms, anaromatic heterocycle having 1 to 9 carbon atoms and up to 3 heteroatomsselected from the group consisting of S, N and O, arylalkyl having 8 to18 carbon atoms, cycloalkyl having 3 to 8 carbon atoms or a radical ofthe formula SO₂R¹³, wherein the aryl radical for its part may be mono-or polysubstituted by halogen, hydroxyl, CN, NO₂, NH₂, NHCOR⁷, alkyl,alkoxy, halogenoalkyl or halogenoalkoxy having up to 6 carbon atoms, ortwo substituents R⁸ and R⁹ or R¹¹ and R¹² may be attached to one anotherforming a five- or six-membered ring which may contain O or N, andwherein R¹³ is straight-chain or branched alkyl having up to 4 carbonatoms or aryl having 6 to 10 carbon atoms, where the aryl radical forits part may be mono- or polysubstituted by halogen, CN, NO₂, alkyl,alkoxy, halogenoalkyl or halogenoalkoxy having up to 6 carbon atoms, R¹⁰is hydrogen, straight-chain or branched alkyl having up to 12 carbonatoms, straight-chain or branched alkenyl having up to 12 carbon atoms,aryl having 6 to 10 carbon atoms, an aromatic heterocycle having 1 to 9carbon atoms and up to 3 heteroatoms selected from the group consistingof S, N and O, or cycloalkyl having 3 to 8 carbon atoms, which mayfurthermore optionally be substituted by halogen, hydroxyl, CN, NO₂,NH₂, NHCOR⁷, alkyl, alkoxy, halogenoalkyl or halogenoalkoxy having up to6 carbon atoms; and/or the cyclic radicals in Y may in each case bemono- to trisubstituted by aryl having 6 to 10 carbon atoms, or by anaromatic or saturated heterocycle having 1 to 9 carbon atoms and up to 3heteroatoms selected from the group consisting of S, N and O, which mayalso be attached via N, which may be attached directly or via a group O,S, SO, SO₂, NR⁷, SO₂NR⁷, CONR⁷, straight-chain or branched alkylene,straight-chain or branched alkenediyl, straight-chain or branchedalkyloxy, straight-chain or branched oxyalkyloxy, straight-chain orbranched sulphonylalkyl, straight-chain or branched thioalkyl having ineach case up) to 8 carbon atoms and which may be mono- to trisubstitutedby straight-chain or branched alkyl, straight-chain or branched alkoxy,straight-chain or branched alkoxyalkoxy, straight-chain or branchedhalogenoalkyl, straight-chain or branched halogenoalkoxy, carbonylalkylor straight-chain or branched alkenyl having in each case up to 6 carbonatoms, halogen, SR⁶, CN, NO₂, NR⁸R⁹, CONR¹⁵R¹⁶or NR¹⁴COR¹⁷, in which R¹⁴is hydrogen, straight-chain or branched alkyl having up to 8 carbonatoms or cycloalkyl having 3 to 8 carbon atoms, R¹⁵, R¹⁶ independentlyof one another are hydrogen, straight-chain or branched alkyl having upto 8 carbon atoms, cycloalkyl having 3 to 8 carbon atoms, aryl having 6to 10 carbon atoms or a radical of the formula SO₂R¹⁸, where the arylradical for its part may be mono- or polysubstituted by halogen,hydroxyl, CN, NO₂, NH₂, NHCOR⁷, alkyl, alkoxy, halogenoalkyl orhalogenoalkoxy having up to 6 carbon atoms, in which R¹⁸ isstraight-chain or branched alkyl having up to 4 carbon atoms or arylhaving 6 to 10 carbon atoms, where the aryl radical for its part may bemono- or polysubstituted by halogen, hydroxyl, CN, NO₂, NH₂, NHCOR⁷,alkyl, alkoxy, halogenoalkyl or halogenoalkoxy having up to 6 carbonatoms, and R¹⁷ is hydrogen, straight-chain or branched alkyl having upto 12 carbon atoms, straight-chain or branched alkenyl having up to 12carbon atoms, aryl having 6 to 10 carbon atoms, an aromatic heterocyclehaving 1 to 9 carbon atoms and up to 3 heteroatoms selected from-thegroup consisting of S, N and O, or cycloalkyl having 3 to 8 carbonatoms, which may furthermore optionally be substituted by halogen,hydroxyl, CN, NO₂, NH₂, NHCOR⁷, alkyl, alkoxy, halogenoalkyl orhalogenoalkoxy having up to 6 carbon atoms; and/or the cyclic radicalsin Y may be fused with an aromatic or saturated carbocycle having 1 to10 carbon atoms or an aromatic or saturated heterocycle having 1 to 9carbon atoms and up to 3 heteroatoms selected from the group, consistingof S, N and O, R³ is hydrogen, halogen, straight-chain or branchedalkyl, straight-chain or branched halogenoalkyl, straight-chain orbranched alkoxy, or alkoxycarbonyl having in each case up 2 to 4 carbonatoms, or CN, NO₂ or NR¹⁹R²⁰, in which R¹⁹ and R²⁰ independently of oneanother are hydrogen, straight-chain or branched alkyl having up to 4carbon atoms or cycloalkyl having 3 to 8 carbon atoms, m is an integerfrom 1 to 4, W is straight-chain or branched alkylene having up to 6carbon atoms or straight-chain or branched alkenediyl having up to 6carbon atoms, which may in each case contain a group selected from thegroup consisting of O, S(O)_(g), NR²¹, CO and CONR²¹, or is CO, NHCO orOCO, in which q is 0, 1 or 2, R²¹ is hydrogen, straight-chain orbranched alkyl having up to 8 carbon atoms or cycloalkyl having 3 to 8carbon atoms, U is straight-chain or branched alkyl having up to 4carbon atoms, A is aryl having 6 to 10 carbon atoms or an aromaticheterocycle having 1 to 9 carbon atoms and up to 3 heteroatoms selectedfrom the group consisting of S, N and O, which may optionally be mono-to trisubstituted by halogen, straight-chain or branched alkyl,straight-chain or branched halogenoalkyl, straight-chain or branchedalkoxy, halogenoalkoxy or alkoxycarbonyl having up to 4 carbon atoms,CN, NO₂ or NR²²R²³, in which R²² and R²³ independently of one anotherare each hydrogen, straight-chain or branched alkyl having up to 8carbon atoms or cycloalkyl having 3 to 8 carbon atoms, carbonylalkyl orsulphonylalkyl, R² is tetrazolyl, COOR²⁴ or CONR²⁵R²⁶, in which R²⁴ ishydrogen, alkyl having 1 to 8 carbon atoms or cycloalkyl having 3 to 8carbon atoms, R²⁵ and R²⁶ independently of one another are eachhydrogen, straight-chain or branched alkyl having up to 8 carbon atoms,cycloalkyl having 3 to 8 carbon atoms or a radical of the formulaSO₂R²⁷, or R²⁵ and R²⁶ together form a five- or six-membered ring whichmay contain N or O, in which R²⁷ is straight-chain or branched alkylhaving up to 4 carbon atoms or aryl having 6 to 10 carbon atoms, wherethe aryl radical for its part may be mono- or polysubstituted byhalogen, CN, NO₂, alkyl, alkoxy, halogenoalkyl or halogenoalkoxy havingup to 6 carbon atoms.
 3. A compound of the formula (IV)

in which U is straight-chain or branched alkyl having up to 4 carbonatoms, A is aryl having 6 to 10 carbon atoms or an aromatic heterocyclehaving 1 to 9 carbon atoms and up to 3 heteroatoms selected from thegroup consisting of S, N and O, which may optionally be mono- totrisubstituted by halogen, straight-chain or branched alkyl,straight-chain or branched halogenoalkyl, straight-chain or branchedalkoxy, halogenoalkoxy or alkoxycarbonyl having up to 4 carbon atoms,CN, NO₂ or NR²²R²³, in which R²² and R²³ independently of one anotherare each hydrogen, straight-chain or branched alkyl having up to 8carbon atoms or cycloalkyl having 3 to 8 carbon atoms, carbonylalkyl orsulphonylalkyl, R² is tetrazolyl, COOR²⁴ or CONR²⁵R²⁶, in which R²⁴ ishydrogen, alkyl having 1 to 8 carbon atoms or cycloalkyl having 3 to 8carbon atoms, R²⁵ and R²⁶ independently of one another are eachhydrogen, straight-chain or branched alkyl having up to 8 carbon atoms,cycloalkyl having 3 to 8 carbon atoms or a radical of the formulaSO₂R²⁷, or R²⁵ and R²⁶ together form a five- or six-membered ring whichmay contain N or O, in which R²⁷ is straight-chain or branched alkylhaving up to 4 carbon atoms or aryl having 6 to 10 carbon atoms, wherethe aryl radical for its part may be mono- or polysubstituted byhalogen, CN, NO₂, alkyl, alkoxy, halogenoalkyl or halogenoalkoxy havingup to 6 carbon atoms, X is straight-chain or branched alkylene having upto 12 carbon atoms or straight-chain or branched alkenediyl having up to12 carbon atoms which may in each case contain one to three groupsselected from the group consisting of O, S(O)_(r), NR²⁸, CO and CONR²⁹,or is aryl or aryloxy having 6 to 10 carbon atoms, where the arylradical for its part may be mono- or polysubstituted by halogen, CN,NO₂, alkyl, alkoxy, halogenoalkyI or halogenoalkoxy having up to 6carbon atoms, where optionally any two atoms of the abovementionedchains are attached to one another via an alkyl chain, forming a three-to eight-membered in which r is 0, 1 or 2, R²⁸ is hydrogen, alkyl having1 to 8 carbon atoms or cycloalkyl having 3 to 8 carbon atoms, R²⁹ ishydrogen, straight-chain or branched alkyl having up to 8 carbon atomsor cycloalkyl having 3 to 8 carbon atoms. and R¹ is tetrazolyl, COOR³⁰or CONR³¹R³², in which R³⁰ is hydrogen alkyl having 1 to 8 carbon atomsor cycloalkyl having 3 to 8 carbon atoms, R³¹ and R³² independently ofone another are each hydrogen, straight-chain or branched alkyl havingup to 8 carbon atoms, cycloalkyl having 3 to 8 carbon atoms or a radicalof the formula SO₂R³³, in which R³³ is straight-chain or branched alkylhaving up to 4 carbon atoms or aryl having 6 to 10 carbon atoms, wherethe aryl radical for its part may be mono- or polysubstituted byhalogen, CN, NO, alkyl, alkoxy, halogenoalkyl or halogenoalkoxy havingup to 6 carbon atoms
 4. A compound of the formula (VI)

in which V is absent, O, NR⁴, NR⁴CONR⁴, NR⁴CO, NR⁴SO₂, COO, CONR⁴ orS(O)_(o), in which R⁴ independently of any other radical R⁴ which may bepresent, is hydrogen, straight-chain or branched alkyl having up to 8carbon atoms, cycloalkyl having 3 to 8 carbon atoms, aryl having 6 to 10carbon atoms or arylalkyl having 7 to 18 carbon atoms, where the arylradical for its part may be mono- or polysubstituted by halogen, alkyl,or alkoxy having up to 6 carbon atoms, o is 0, 1 or 2, Q is absent,straight-chain or branched alkylene, straight-chain or branchedalkenediyl or straight-chain or branched alkynediyl, having in each caseup to 12 carbon atoms, which may in each case contain one or more groupsselected from the group consisting of O, S(O)_(p), NR⁵, CO, NR⁵SO₂ andCONR⁵ and which may be mono- or polysubstituted by halogen, hydroxyl oralkoxy having up to 4 carbon atoms, where optionally any two atoms ofthe abovementioned chain may be attached to one another forming a three-to eight-membered ring, in which R⁵ is hydrogen, straight-chain orbranched alkyl having up to 8 carbon atoms or cycloalkyl having 3 to 8carbon atoms, which may be substituted by halogen or alkoxy having up to4 carbon atoms, and p is 0, 1 or 2, Y is hydrogen, NR⁸R⁹, aryl having 6to 10 carbon atoms, an aromatic or saturated heterocycle having 1 to 9carbon atoms and up to 3 heteroatoms selected from the group consistingof S, N and O, or straight-chain or branched cycloalkyl having 3 to 8carbon atoms, which may also be attached via N, wherein the cyclicradicals may in each case be mono- to trisubstituted by straight-chainor branched alkyl, straight-chain or branched alkenyl, straight-chain orbranched alkynyl, straight-chain or branched alkoxy, straight-chain orbranched halogenoalkyl, straight-chain or branched halogenoalkoxy havingin each case up to 8 carbon atoms, straight-chain or branched cycloalkylhaving 3 to 8 carbon atoms, halogen, hydroxyl, CN, SR⁶, NO₂, NR⁸R⁹,NR⁷COR¹⁰, NR⁷CONR⁷R¹⁰ or CONR¹¹R¹², in which R⁶ is hydrogen,straight-chain or branched alkyl having up to 8 carbon atoms,straight-chain or branched halogenoalkyl having up to 8 carbon atoms orcycloalkyl having 3 to 8 carbon atoms, R⁷ independently of any otherradical R⁷ which may be present is hydrogen, straight-chain or branchedalkyl having up to 8 carbon atoms or cycloalkyl having 3 to 8 carbonatoms, R⁸, R⁹, R¹¹ and R¹² independently of one another are hydrogen,straight-chain or branched alkyl, straight-chain or branched alkenylhaving up to 8 carbon atoms, aryl having 6 to 10 carbon atoms, anaromatic heterocycle having 1 to 9 carbon atoms and up to 3 heteroatomsselected from the group consisting of S, N and O, arylalkyl having 8 to18 carbon atoms, cycloalkyl having 3 to 8 carbon atoms or a radical ofthe formula SO₂R¹³, wherein the aryl radical for its part may be mono-or polysubstituted by halogen, hydroxyl, CN, NO₂, NH₂, NHCOR⁷, alkyl,alkoxy, halogenoalkyl or halogenoalkoxy having up to 6 carbon atoms, ortwo substituents R⁸ and R⁹ or R¹¹ and R¹² may be attached to one anotherforming a five- or six-membered ring which may contain O or N, andwherein R¹³ is straight-chain or branched alkyl having up to 4 carbonatoms or aryl having 6 to 10 carbon atoms, where the aryl radical forits part may be mono- or polysubstituted by halogen, CN, NO₂, alkyl,alkoxy, halogenoalkyl or halogenoalkoxy having up to 6 carbon atoms, R¹⁰is hydrogen, straight-chain or branched alkyl having up to 12 carbonatoms, straight-chain or branched alkenyl having up to 12 carbon atoms,aryl having 6 to 10 carbon atoms, an aromatic heterocycle having 1 to 9carbon atoms and up to 3 heteroatoms selected from the group consistingof S, N and O or cycloalkyl having 3 to 8 carbon atoms, which mayfurthermore optionally be substituted by halogen, hydroxyl, CN, NO₂,NH₂, NHCOR⁷, alkyl, alkoxy, halogenoalkyl or halogenoalkoxy having up to6 carbon atoms; and/or the cyclic radicals in Y may in each case bemono- to trisubstituted by aryl having 6 to 10 carbon atoms, or by anaromatic or saturated heterocycle having 1 to 9 carbon atoms and up to 3heteroatoms selected from the group consisting of S, N and O, which mayalso be attached via N, which may be attached directly or via a group O,S, SO, SO₂, NR⁷, SO₂NR⁷, CONR⁷, straight-chain or branched alkylene,straight-chain or branched alkenediyl, straight-chain or branchedalkyloxy, straight-chain or branched oxyalkyloxy, straight-chain orbranched sulphonylalkyl, straight-chain or branched thioalkyl having ineach case up to 8 carbon atoms and which may be mono- to trisubstitutedby straight-chain or branched alkyl, straight-chain or branched alkoxy,straight-chain or branched alkoxyalkoxy, straight-chain or branchedhalogenoalkyl, straight-chain or branched halogenoalkoxy, carbonylalkylor straight-chain or branched alkenyl having in each case up to 6 carbonatoms, halogen, SR⁶, CN, NO₂, NR⁸R⁹, CONR¹⁵R¹⁶ or NR¹⁴COR¹⁷, in whichR¹⁴ is hydrogen, straight-chain or branched alkyl having up to 8 carbonatoms or cycloalkyl having 3 to 8 carbon atoms, R¹⁵R¹⁶ independently ofone another are hydrogen, straight-chain or branched alkyl having up to8 carbon atoms, cycloalkyl having 3 to 8 carbon atoms, aryl having 6 to10 carbon atoms or a radical of the formula SO₂R¹⁸, where the arylradical for its part may be mono- or polysubstituted by halogen,hydroxyl, CN, NO₂, NH₂, NHCOR⁷, alkyl, alkoxy, halogenoalkyl orhalogenoalkoxy having up to 6 carbon atoms, in which R¹⁸ isstraight-chain or branched alkyl having up to 4 carbon atoms or arylhaving 6 to 10 carbon atoms, where the aryl radical for its part may bemono- or polysubstituted by halogen, hydroxyl, CN, NO₂, NH₂, NHCOR⁷,alkyl, alkoxy, halogenoalkyl or halogenoalkoxy having up to 6 carbonatoms, and R¹⁷ is hydrogen, straight-chain or branched alkyl having upto 12 carbon atoms, straight-chain or branched alkenyl having up to 12carbon atoms, aryl having 6 to 10 carbon atoms, an aromatic heterocyclehaving 1 to 9 carbon atoms and up to 3 heteroatoms selected from thegroup consisting of S, N and O, or cycloalkyl having 3 to 8 carbonatoms, which may furthermore optionally be substituted by halogen,hydroxyl, CN, NO₂, NH₂, NHCOR⁷, alkyl, alkoxy, halogenoalkyl orhalogenoalkoxy having up to 6 carbon atoms; and/or the cyclic radicalsin Y may be fused with an aromatic or saturated carbocycle having 1 to10 carbon atoms or an aromatic or saturated heterocycle having 1 to 9carbon atoms and up, to 3 heteroatoms selected from the group consistingof S, N and O, R³ is hydrogen, halogen, straight-chain or branchedalkyl, straight-chain or branched halogenoalkyl, straight-chain orbranched alkoxy, or alkoxycarbonyl having in each case up to 4 carbonatoms, or CN, NO₂ or NR¹⁹R²⁰, in which R¹⁹ and R²⁰ independently of oneanother are hydrogen, straight-chain or branched alkyl having up to 4carbon atoms or cycloalkyl having 3 to 8 carbon atoms, m is an integerfrom 1 to 4, W is straight-chain or branched alkylene having up to 6carbon atoms or straight-chain or branched alkenediyl having up to 6carbon atoms, which may in each case contain a group selected from thegroup consisting of O, S(O)_(q), NR²¹, CO and CONR²¹, or is CO, NHCO orOCO, in which q is 0, 1 or 2, R²¹ is hydrogen, straight-chain orbranched alkyl having up, to 8 carbon atoms or cycloalkyl having 3 to 8carbon atoms, X is straight-chain or branched alkylene having up to 12carbon atoms or straight-chain or branched alkenediyl having up to 12carbon atoms which may in each case contain one to three groups selectedfrom the group consisting of O, S(O)_(r), NR²⁸, CO and CONR²⁹, or isaryl or aryloxy having 6 to 10 carbon atoms, where the aryl radical forits part may be mono- or polysubstituted by halogen, CN, NO₂, alkyl,alkoxy, halogenoalkyl or halogenoalkoxy having up to 6 carbon atoms,where optionally any two atoms of the abovementioned chains are attachedto one another via an alkyl chain, forming a three- to eight-membered inwhich r is 0, 1 or 2, R²⁸ is hydrogen, alkyl having 1 to 8 carbon atomsor cycloalkyl having 3 to 8 carbon atoms, R²⁹ is hydrogen,straight-chain or branched alkyl having up to 8 carbon atoms orcycloalkyl having 3 to 8 carbon atoms, and R¹ is tetrazolyl, COOR³⁰ orCONR³¹R³², in which R³⁰ is hydrogen, alkyl having 1 to 8 carbon atoms orcycloalkyl having 3 to 8 carbon atoms, R³¹ and R³² independently of oneanother are each hydrogen, straight-chain or branched alkyl having up to8 carbon atoms, cycloalkyl having 3 to 8 carbon atoms or a radical ofthe formula SO₂R³³, in which R³³ is straight-chain or branched alkylhaving up to 4 carbon atoms or aryl having 6 to 10 carbon atoms, wherethe aryl radical for its part may be mono- or polysubstituted byhalogen, CN, NO₂, alkyl, alkoxy, halogenoalkyl or halogenoalkoxy havingup to 6 carbon atoms.